Systems, devices and methods relating to endocardial pacing for resynchronization

ABSTRACT

Disclosed are certain methods, apparatus, and processor-readable mediums that may be used to treat a conduction abnormality of the heart. In one example, the apparatus includes an implantable pacing profile generator configured to generate a specified pacing electrostimulation profile for delivery to a heart via electrodes located near a septal region of the right ventricle of the heart near the His bundle, the pacing profile including a first pulse for delivery via a first electrode; and a second pulse for delivery via a second electrode; and wherein the first and second pulses are at least partially concurrent in time and opposite in polarity to each other.

CLAIM OF PRIORITY

This application is a continuation of and claims the benefit of priorityunder 35 U.S.C. §120 to Zhu et al., U.S. patent application Ser. No.12/147,293, entitled “Systems, Devices And Methods Relating ToEndocardial Pacing For Resynchronization,” filed on Jun. 26, 2008(Attorney Docket No. 279.H27US1), which in turn is acontinuation-in-part of and claims priority under 35 U.S.C. §120 to bothU.S. patent application Ser. No. 11/300,611, filed Dec. 13, 2005(Ventricular Pacing) to Daniel Felipe Ortega et al. (AMED.002PA), nowissued as U.S. Pat. No. 7,512,440 and to U.S. patent application Ser.No. 11/300,242, filed Dec. 13, 2005 (Pacemaker Which Reestablishes OrKeeps The Physiological Electric Conduction Of The Heart And A Method OfApplication) to Daniel Felipe Ortega et al. (AMED.003PA), which in turnclaim priority to Argentine Patent Application Ser. No. 20040104782,filed Dec. 20, 2004, (A New Pacemaker Which Reestablishes Or Keeps ThePhysiological Electric Conduction Of The Heart And A Method OfApplication) to Daniel Felipe Ortega et al.; the benefit of priority ishereby presently claimed to each of the above, and each of which ishereby incorporated by reference herein in its respective entirety.

This patent document claims the benefit, under 35 U.S.C. §119(e), ofU.S. Provisional Patent Applications concurrently filed on Jun. 29,2007, to Qingsheng Zhu and identified by the following Ser. Nos.60/947,308 (Endocardial Pacing For Resynchronization), 60/947,310(Directable Sheath Arrangement For Ventricular Resynchronization),60/947,322 (System And Method For Ventricular Pacing With Monitoring AndResponsiveness To Pacing Effectiveness), 60/947,327 (Electrical CircuitArrangement And Method For Pulse Control Of Endocardial Pacing ForResynchronization), 60/947,336 (Endocardial Pacing For ResynchronizationAnd Defibrillator), 60/947,342 (Endocardial Pacing For ResynchronizationAnd Treatment Of Conduction Abnormalities), and of U.S. ProvisionalPatent Application identified by Ser. No. 61/020,511, filed on Jan. 11,2008 (A Cardiac Stimulation Catheter With Two Contacting Electrodes ToThe Cardiac Tissue And Its Connections To The Stimulator) to QingshengZhu et al.; the benefit of priority is hereby presently claimed to eachof the above, and each of which is hereby incorporated by reference inits respective entirety.

FIELD OF THE INVENTION

This invention generally relates to systems, devices and methodsrelating to cardiac monitoring and treatments such as ventricularpacing. More particular aspects of this invention specifically concernachieving mechanically and/or electrically synchronous contractionswhile pacing of a patient's left and right ventricles by one or moreelectrodes residing in the patient's right ventricle.

BACKGROUND

Pacemakers are perhaps the most well known devices that provide chronicelectrical stimulus, such as cardiac rhythm management. Pacemakers havebeen implanted for medical therapy. Other examples of cardiacstimulators include implantable cardiac defibrillators (ICDs) andimplantable devices capable of performing pacing and defibrillatingfunctions. Such implantable devices provide electrical stimulation toselected portions of the heart in order to treat disorders of cardiacrhythm. An implantable pacemaker paces the heart with timed pacingpulses. The pacing pulses can be timed from other pacing pulses orsensed electrical activity. If functioning properly, the pacemaker makesup for the heart's inability to pace itself at an appropriate rhythm inorder to meet metabolic demand by enforcing a minimum heart rate. Somepacing devices synchronize pacing pulses delivered to different areas ofthe heart in order to coordinate the contractions. Coordinatedcontractions allow the heart to pump efficiently while providingsufficient cardiac output. Clinical data has shown that cardiacresynchronization, achieved through synchronized biventricular pacing,results in a significant improvement in cardiac function. Cardiacresynchronization therapy improves cardiac function in heart failurepatients. Heart failure patients have reduced autonomic balance, whichis associated with LV (left-ventricular) dysfunction and increasedmortality.

Commonly treated conditions relate to the heart beating too fast or tooslow. When the heart beats too slow, a condition referred to asbradycardia, pacing can be used to increase the intrinsic heart rate.When the heart beats too fast, a condition referred to as tachycardia,pacing can be used to reduce the intrinsic heart rate by, for example,inhibiting electrical signals used to generate a contraction of theheart.

When pacing for bradycardia, percutaneously placed pacing electrodes arecommonly positioned in the right-side chambers (right atrium or rightventricle) of the heart. Access to such chambers is readily availablethrough the superior vena cava, the right atrium and then into the rightventricle. Electrode placement in the left ventricle is normallyavoided, where access is not as direct as in right ventricle placement.Moreover, emboli risk in the left ventricle is greater than in the rightventricle. Emboli which might develop in the left ventricle by reason ofthe electrode placement have direct access to the brain via the aortafrom the left ventricle. This presents a significant risk of (cerebral)stroke. Pacing of both the right atrium and right ventricle wasdeveloped. Such dual chamber pacing resulted in better hemodynamicoutput than right ventricle-only pacing. In addition to treatingbradycardia, dual chamber pacing maintained synchrony between the(atrial and ventricle) chambers.

Recent clinical evidence suggests that conventional ventricular pacingfrom the right ventricle creates asynchronous contraction of the leftand right ventricles, thereby resulting in inefficient mechanicalcontraction and reduced hemodynamic performance. Long term rightventricular pacing has even been found to be associated with anincreased risk of developing or worsening heart failure.

SUMMARY

The present invention is directed to overcoming the above-mentionedchallenges and others related to the types of tools and methodsdiscussed above and in other implementations. The present invention isexemplified in a variety of implementations and applications, many ofwhich involve tools and methods helpful, or particularly suited, forcertain cardiac conditions advantaged by pacing of the right and leftventricles from a lead in the right ventricle. Generally, suchventricular pacing is used to facilitate mechanically and/orelectrically synchronous contractions for resynchronization.

Some aspects of the present invention, presented herein as mere examplesand without limitation, involve pacing and/or mapping by deliveringpulses to a cardiac site useful for improving heart function asmeasured, e.g., by QRS width, fractionation, late LV activation timing,mechanical synchronicity of free wall and septal wall, effectivethroughput/pressure, and by any combination thereof. Other specificaspects, which can be implemented alone or in combination, include:determining a pacing (voltage) threshold, beyond the capture threshold,to improve heart function; delivering pulses of opposite polarity toachieve such heart-function improvement; bi-ventricular pacing from alead in the right ventricle for such improved heart function; deliveringpulses of opposite polarity at a site near the His bundle;electrode-based His-pacing, without penetrating the myocardium with anpacing electrode; generating and/or delivering multiple pacing profiles,e.g., by iterating through different pacing profiles, including a pacingprofile that delivers pulses of opposite polarity and another pacingprofile; delivering a pacing profile to generate a synchronouscontraction of the septal wall and free wall of the LV from a RV(right-ventricle) pacing location; and treating one or more of distalLBBB (left bundle branch block) and/or diffuse LBBB by pacing at a sitenear the His bundle.

The skilled artisan will appreciate that the His bundle is acontinuation of the atrioventricular (AV) bundle and previouslycharacterized as an area of heart muscle cells that provide electricalconduction for transmitting the electrical impulses from an area nearthe AV node (located between the atria and the ventricles). Inconnection with implementations of the present invention, it has beendiscovered that certain cells in and around the His bundle can bemanipulated to respond to certain electrical stimulus in unexpectedways. Some aspects and implementations of the present inventionfacilitate modulation of the His bundle to improve the heart conditionin unexpected ways.

Implementations of the present invention take a wide variety of forms,e.g., ranging from devices, systems, methods of using and manufacturingsuch devices and systems, to computer-accessible data (computerexecutable instructions and other input and output data) useful forimplementing such methods, devices and systems. Many of theseimplementations involve such tools and steps relating to theabove-listed aspects.

As specific examples of such implementations, the present invention canbe implemented in the form of methods, devices and arrangements ofdevices for monitoring cardiac operation and modifying cardiacoperation, e.g., for cardiac treatment. In one such specific exampleembodiment, one or more of the above aspects involves placement of anelectrode arrangement (including at least one electrode) in a RV of theheart for capturing the myocardium for re-synchronization of the leftand right ventricles. This is achieved by providing first and secondsignal components having opposite polarity on respective electrodes. Thecontraction of the heart is monitored and used in determining theposition of the electrodes. In more specific embodiments, the electrodearrangement is located in the sweet spot (locus) for achievingresynchronization, in the septal part of the RV endocardium. Anodalpacing of one of the electrodes can be used with respect to a referencevoltage in the body of the patient to achieve resynchronization or asynchronous contraction during pacing of the heart. Polarities may beswitched as appropriate (e.g., once every few hours) to avoid anodalblock (the rise of stimulation thresholds that occurs after continuousanodal stimulation at the anodal electrode).

In other specific examples, implementations involve pacing from theright ventricle to treat LBBB, diffuse-distal block characterized bylarge QRS width (e.g., QRS>120 ms) and fractionated ECG(electrocardiograph or electrocardiogram) signals. Consistent therewith,a specific method involves the use of a pacing profile havingopposite-polarity pulses (relative to body common) delivered for acardiac capture (defined as the presence of contractions in the heart indirect response to electrical stimulation signals from an externalsource). In various contexts, such a pacing profile is referred toherein as an “Xstim” pacing profile or simply as Xstim.

One such Xstim pacing profile includes the use of two electrodes thatare oppositely charged with respect to a reference electrode. In variousimplementations, the electrodes are spatially disparate. The pulses canbe provided, relative to one another, in phase, out of phase, offset andoverlapping, offset not overlapping with no delay between pulses, offsetnot overlapping with a delay between pulses or biphasic with a singleelectrode near the His bundle.

In yet other specific examples, implementations involve devices andmethods for pacing and/or mapping at a location near the bundle of Hisin the right ventricle. As indicated above, the location ischaracterized by one or more of improvement in QRS width, improvement infractionation (using an ECG) or movement of late activated LV locationforward in the QRS. In one instance, the pacing is delivered with asingle pacing lead and both ventricles are captured. In some instances,the pacing can use an Xstim pacing profile.

According to yet other embodiments, the present invention involvespacing at a location that is determined as follows. An intrinsic orbaseline ECG reading is taken. A pacing lead is placed in the RV nearthe bundle of His. A pacing signal is delivered to the pacing lead. In aspecific instance, the pacing signal is an Xstim pacing profile. Apacing ECG signal is taken. Comparisons are made between one or more ofthe QRS width, fractionated QRS and the timing of a late activatedregion of LV relative to the QRS. The position of the probe is changedand the pacing and comparison steps are repeated as necessary. The leadcan then be fixed at the appropriate location.

In other embodiments, the present invention involves selection of apacing profile and placing a lead in the RV at or near the His bundle todeliver a plurality of pacing profiles. Heart function is recorded(e.g., using an ECG), and a suitable pacing profile is then selected fortreatment.

According to another embodiment, pacing devices and methods of usingsuch devices involve a catheter that delivers a lead that has twoelectrodes. In certain implementations thereof, the catheter is adaptedto contact near the His bundle. A pacing profile (with two oppositevoltages, referenced to body common) is delivered to the electrodes. Theelectrodes are individually addressable and spatially disparate. In aspecific instance, one electrode is located at or near the distal tip ofthe lead and the other is located between the distal tip and theproximal end of the lead. Some embodiments allow for the use of morethan two electrodes. Also, one or more electrodes may be used to senseheart function.

According to another embodiment, a catheter is adapted and used tofacilitate adjustment of the location along the septal wall of the rightventricle. The catheter is designed for delivering a pacing profile andfor subsequent adjustment of a delivery site for the pacing profile.This embodiment can be useful for a pace-sense-adjust procedure which,in some instances, is iterated until a location is determined forachieving the improved heart function. In a specific instance, thecatheter includes a removable outer sheath. An inner portion can beextended from the outer sheath. The outer sheath can be used to directthe inner portion. In one instance, the outer sheath allows foradjustment of a curvature of the sheath. Once properly located, theinner portion can be extended to fix to the proper location. Tines orscrews can be used in connection with the extension from the innerportion of the sheath.

Aspects of the present invention lend themselves to synchronous pacingof the left and right ventricles from a single lead. In a specificinstance, the lead has only two electrodes.

According to an embodiment of the present invention, methods ofmanufacturing the devices disclosed herein and devices for implementingthe methods discussed herein are implemented.

According to an embodiment of the present invention, a system isimplemented. The system can include an implantable pacing device, acatheter used to place a pacing lead and a heart function feedbackmechanism for assessing results of pacing using the implantable device.

According to an embodiment of the present invention, devices and/ormethods are implemented for allowing selectively implementable Xstimpacing and biventricular pacing.

As previously indicated, the above-discussed aspects and examples arenot to be treated as limiting the scope or teachings of the disclosureherein. The skilled artisan would appreciate that, partly based on thevarious discoveries identified herein, the present invention can beembodied in many ways including but not limited to the above-discussedaspects and examples.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention may be more completely understood in considerationof a detailed discussion of various example embodiments, described inaccordance with the present invention, as presented hereinafter inconnection with the following figures, each of which is consistent withthe present invention:

FIG. 1 is a schematic cross-sectional view of the heart showing relevantanatomical features and schematically showing a catheter with pacingelectrodes in the right ventricle and a subcutaneously placedimplantable pulse generator;

FIG. 2 is the view of FIG. 1 showing electrodes in contact with a septalwall;

FIG. 2A is a cross-sectional view of an electrode lead showing amechanism for attachment of an electrode to a septal wall;

FIG. 3 is the view of FIG. 1 showing an electrode lead formed, in part,from shape memory alloys for urging electrodes against a septal wall;

FIG. 4 is the view of FIG. 1 showing a further embodiment of anelectrode lead for urging electrodes against a septal wall;

FIG. 5 is the view of FIG. 1 showing electrodes on a septal wall andenergized by wireless transmission;

FIG. 6 is the view of FIG. 5 showing electrodes embedded within theseptal wall;

FIG. 7 is the view of FIG. 4 showing the lead of FIG. 4 with multipleelectrodes urged against the septal wall;

FIG. 7A is the view of FIG. 1 showing a conventional active fixationlead with a helix for attachment of the tip electrode to a septal wall;

FIG. 7B is the view of FIG. 1 showing a shocking electrode;

FIG. 8 is a view, taken in cross-section, of right and left ventriclesof a heart showing the electrodes of FIG. 1 (without showing the leadbody) energized to create electromagnetic fields;

FIG. 9 is the view of FIG. 8 showing the field shifted toward the leftventricle in response to repositioning of leads;

FIG. 10 is the view of FIG. 8 showing the field distorted toward a freewall of the left ventricle by influence of an external referenceelectrode;

FIG. 11 is the view of FIG. 9 with a reference electrode placed withinthe left ventricle;

FIG. 12 is the view of FIG. 14 with an external electrode placed on theepicardial surface of the heart;

FIG. 13 is a view with an external electrode placed within a coronarysinus;

FIG. 14 is the view of FIG. 9 with fields distorted to be biased towardthe left ventricle by the addition of dielectric material on a side ofthe electrodes of FIG. 9;

FIG. 15 shows a field distorted towards an upper end of the free wall inresponse to a reference electrode in a first position;

FIG. 16 is the view of FIG. 15 with a reference electrode switched to asecond position;

FIG. 17 is the view of FIG. 15 with a reference electrode replaced bytwo polarized electrodes;

FIG. 18 is a graphical representation of pulsed waveforms to be appliedby first and second electrodes of the various embodiments;

FIG. 18A is a view similar to that of FIG. 18 showing alternativewaveforms;

FIG. 18B is a view similar to that of FIG. 18 and showing two electrodescreating two separate fields to a reference electrode;

FIG. 19 is an electrical schematic for a portion of a pacing outputdesired in a pulse generator with programmable pacing configurations;

FIG. 20 is a side elevation view of a patient's head and neck showingapplication of the present invention to applying a pacing signal to avagus nerve;

FIG. 21 is a system for determining optimal placement of the electrodes;

FIG. 22 is a view showing the spacing of two electrodes;

FIGS. 23A, 23B, 23C and 23D depict a graphical representation of pulseto be applied by the electrodes of the various embodiments;

FIG. 24 is diagram of a directable/adjustable catheter-type deviceuseful for delivering certain pulsed waveforms;

FIGS. 24A, 24B, 24C and 24D depict a graphical representation of pulsedwaveforms to be applied by the electrodes of the various embodiments;

FIG. 25 depicts intrinsic activity compared to Xstim created activitymeasured by an ECG;

FIG. 26 shows intrinsic activity compared to Xstim created activitymeasured by a 12 lead ECG recordings;

FIG. 27 shows intrinsic activity compared to Xstim created activitymeasured by ECG recordings;

FIG. 28 shows comparisons of Xstim pacing and intrinsic pacing;

FIG. 29 shows respective sets of baseline and Xstim results for the CS(coronary sinus) activation time;

FIG. 30 shows the measurements of asynchrony obtained via echo imagingof a plurality of patients with respect to a baseline and Xstim pacing;

FIGS. 31A and 31B are graphs useful in showing a comparison of Xstimpacing on global left ventricle function as defined by the change inpressure per unit of time measured in dp/dt (change in pressure/changein time);

FIG. 32 shows the change in pressure rate during biventricular pacing asa function of the baseline QRS width in comparison with the response toXstim pacing;

FIG. 33 shows bursts of Xstim pacing and intrinsic pacing as well as theresulting intraventricular pressure of the left ventricle;

FIG. 34 shows the stability of the rate of change in the pressure of theleft ventricle during Xstim pacing;

FIG. 35 shows the stability of the rate of change in the pressure of theleft ventricle during Xstim pacing

FIG. 36 represents the decrease in the rate of change in pressure seenwhen Xstim pacing is stopped;

FIG. 37 represents the decrease in the rate of change in pressure seenwhen

Xstim pacing is stopped;

FIG. 38 represents the decrease in the rate of change in pressure seenwhen Xstim pacing is stopped;

FIG. 39 represents the decrease in the rate of change in pressure seenwhen Xstim pacing is stopped;

FIG. 40 shows the change in the CS activation time relative to the QRScomplex for baseline and Xstim pacing;

FIG. 41 shows QRS improvement and pressure increases during XSTIM pacingat 3.5 V;

FIG. 42 shows QRS improvement in narrowing and pressure improvement forXstim pacing at 5 V for the same patient as FIG. 41;

FIG. 43 shows minimum and maximum rate of pressure change (dp/dt)between the Xstim pacing and baseline;

FIG. 44 shows the rate of pressure change as correlated to the R-to-Rinterval (of the QRS complex) between beats of the heart;

FIGS. 45A, 45B, 45C and 45D depict example procedures for determiningpacing-lead placement;

FIG. 46 shows a cross-sectional view of a heart and the Hisian andpara-hisian regions, consistent with an embodiment of the presentinvention;

FIG. 47 shows a cross-sectional view of the heart marked with pacingsites;

FIG. 48 shows pacing site locations on a 3-D depiction of the union ofthe AV node, the para-hisian and Hisian regions;

FIG. 49 shows pacing site locations on cross-sectional views of theheart; and

FIG. 50 shows an example circuit for providing various stimulationprofiles.

While the invention is amenable to various modifications and alternativeforms, various embodiments have been shown by way of example in thedrawings and will be described in detail. It should be understood,however, that the intention is not to limit the invention to theparticular embodiments described. On the contrary, the intention is tocover all modifications, equivalents, and alternatives falling withinthe spirit and scope of the invention.

DETAILED DESCRIPTION

The present invention is believed to be applicable to a variety ofdifferent types of devices and approaches, and the invention has beenfound to be particularly suited for approaches to pacing of the rightand left ventricles from a lead in the right ventricle. In certainimplementations, the invention is used to facilitate mechanically and/orelectrically synchronous contractions for resynchronization where theleft ventricle has regained its ability to rapidly contract due toconduction abnormalities such as LBBB. While the present invention isnot necessarily limited to such applications, various aspects of theinvention may be appreciated through a discussion of various examplesusing this context.

Consistent with specific embodiments and various discoveries realized inconnection with the present invention, heart function can be improved bypacing and/or mapping by delivering pulses to a cardiac site, where theheart function is indicated or measured, e.g., by QRS width,fractionation, late LV activation timing, mechanical synchronicity offree wall and septal wall, effective throughput/pressure, and/or by anycombination thereof. Certain methods and specific aspects consistentwith such embodiments of the present invention include: determining apacing (voltage) threshold, beyond the capture threshold, to improveheart function; delivering pulses of opposite polarity to achieve suchheart-function improvement; bi-ventricular pacing from a lead in theright ventricle for such improved heart function; delivering pulses ofopposite polarity at a site near the His bundle; electrode-basedHis-pacing, without penetrating the myocardium (with a pacingelectrode); generating and/or delivering multiple pacing profiles, e.g.,by iterating through different pacing profiles, including a pacingprofile that delivers pulses of opposite polarity and another pacingprofile; delivering a pacing profile to generate a synchronouscontraction of the septal wall and free wall of the LV from a RV(right-ventricle) pacing location; and treating one or more of distalLBBB (left bundle branch block) and/or diffuse LBBB by pacing at a sitenear the His bundle.

As a specific example of an unexpected result, it has been discoveredthat His bundle pacing and/or parahisian pacing can be used to treatpatients exhibiting a variety of cardiac abnormalities previouslythought to be unsuitable for His bundle pacing (e.g., large QRScomplexes due to distal left bundle blocks or diffuse left bundleblocks). It has also been discovered that implantation complexities(e.g., duration and/or invasiveness) can be beneficially affected by theuse of specific devices, systems and placement methods.

According to an example embodiment of the present invention, aspecialized stimulation profile is used to capture a synchronouscontraction of the left and right ventricles. The stimulation profile isprovided to a lead in the right ventricle. The lead placement andstimulation profile are selected in response to sensed heart functionduring the pacing. In particular, the lead placement and stimulationprofile are determined based upon more than whether theplacement/profile results in capture (e.g., QRS width or late activationsite timing). In certain instances, this can result in pacingvoltages/profiles not otherwise believed to be desirable (e.g., voltagesderived from criteria other than the capture threshold and/or His bundlepacing without penetrating the surrounding (fibrous) tissue with apacing lead).

The understanding of various implementations of the present inventioncan be facilitated with a discussion of existing pacing, implantationand related procedures and devices. While a substantial number ofdifferences exist between various embodiments of the present inventionand such existing pacing, the present invention does not excludeimplementations that include aspects of existing pacing. Quite to thecontrary, aspects of the present invention are particularly useful forimplementing in conjunction with existing pacing methods and devices.Accordingly, a number of embodiments of the present invention providethe flexibility to be useful when combined with existingimplementations, some of which are discussed hereafter.

Combined pacing of the right ventricle and right atrium has beenperformed by advancing two electrode leads through the superior venacava into the right atrium. The first of these terminated at one or moreelectrodes which were attached to the endocardium of the atrium. Thesecond lead (also having one or more electrodes) was advanced into theright ventricle with the electrode attached to the endocardium of theright ventricle.

Such dual chamber pacing was not without complications. The use of twoleads resulted in a doubling of volume of the vasculature (e.g., thesuperior vena cava and jugular vein) occupied by such leads. Further,attachment of an electrode to the atrial wall was unreliable.

The problems of the dual chamber pacing led to the development ofso-called “single pass” leads. Such leads have both the atrial andventricle electrodes on a common lead.

An example of a single pass lead, for pacing both the right ventricleand right atrium, is taught in U.S. Pat. No. 6,230,061 B1 to Hartungissued May 8, 2001. The lead of the '061 patent is described as afloating lead in that the lead and electrodes are not attached to thewalls of the heart. In one embodiment of the '061 patent (FIG. 4A), twoelectrodes in the right atrium pace the right atrium. In a secondembodiment (FIG. 4B), an electrode resides in the right ventricle to addright ventricular pacing. As will be described, the '061 patentdescribes an oppositely polarized electrode (which may be exposed on asubcutaneously placed implantable pulse generator).

It is believed that the design of the '061 patent has not enjoyed greatcommercial success. This is believed to be due, at least in part, to theseparate development of smaller profile leads and more reliable atrialattachment techniques. Both of these developments address the problemsof dual chamber pacing otherwise addressed by the '061 patent.

When treating for tachycardia (fast heart rate), electrical pulses areused to disrupt a contraction of the heart. This may be effective atreducing the heart rate by disrupting the abnormally fast pulsesgenerated by cardiac dysfunction tissue.

Congestive heart failure (CHF) patients suffer from low left ventricularoutput. CHF is an extremely serious and progressive disease. While drugtreatments exist, they may delay but do not stop or reverse the disease.

CHF patients face a progression of a debilitating condition whichdrastically alters lifestyle and will ultimately be fatal in the absenceof heart transplant. Unfortunately, many patients do not qualify forsuch transplants and the available number of donor hearts is inadequateto treat those who do qualify.

Many CHF patients have low left ventricular output due to a mismatchbetween contractile forces produced by muscles of the left and rightventricles' free wall (the external wall of the left and rightventricles) and the opposing septum (the wall dividing the right andleft ventricles). Ideally, the free wall and septum contract insynchrony during systole to urge blood through the aortic valve. Whenout of synchrony, the septal wall may be contracting while the free wallis relaxed. Instead of urging blood flow, at least a portion of thecontractile energy of the septum is wasted.

The mismatch of free wall and septal contractility is believed to be dueto disorders in the electrical conduction systems of the heart. Thisconduction system includes the A-V node (heart tissue between the atriaand the ventricles that conducts contractile impulses from the atria tothe ventricles), the bundle of His and the Purkinje fibers.

Located at the upper end of the septum, the sinus node creates thesynchronized neuraly-mediated signal for cardiac pacing. These signalsare conducted by the specialized fibers comprising the A-V node and thebundle of His (extending along the length of the septum) and furtherconducted to the muscle of the heart through the Purkinje fibers. ThePurkinje fibers originate in the septum and extend through the apex ofthe heart and to the exterior walls of the heart including into and upthe free wall of the left and right ventricles.

In a healthy heart, the signal flow from the A-V node to the free wallof the left and right ventricles is rapid to ensure the free wall andseptum contract in synchrony. For example, a stimulating signal may flowto the free wall in about 70-90 milliseconds. In patients withconduction abnormalities, this timing may be significantly delayed (to150 milliseconds or more) resulting in asynchronous contraction.

In some patients, the conduction path through the Purkinje fibers may beblocked. The location of the block may be highly localized (as in thecase of so-called “left bundle branch block” or LBBB) or may include anenlarged area of dysfunctional tissue (which can result frominfarction). In such cases, all or a portion of the free wall of theleft and/or right ventricles is flaccid while the septum is contracting.In addition to contributing to asynchronous contraction, the contractionforce of the free wall can increase due to the increase in preload(Starling law) created by the prestretching due to early septalcontraction. This can have a negative overall effect on global function.Such continuous overload of the late activation region can trigger geneprograms of growth, that through a maladaptive process end upaccelerating the remodeling and chamber dilation, further worseningglobal function.

To address asynchronous contraction, CHF patients can be treated withcardiac pacing of the left ventricle. Such pacing includes applying astimulus to the septal muscles in synchrony with stimulation applied tothe muscles of the free wall of the left ventricle. While infarctedtissue will not respond to such stimulus, non-infarcted tissue willcontract thereby heightening the output of the left ventricle byre-synchronizing the contraction. Accordingly, treatment of CHF is oftendirected re-synchronization of the myocardium, whereas other ventricularpacing solutions, such as tachycardia and bradycardia, treat heart rateissues. Dual chamber pacing (right and left ventricles) is notcompletely coordinated when it propagates using cell to cell conductionrather than the specialized His/Purkinje system, thus creating anon-negligible level of asynchrony even in normal hearts.

For various reasons the techniques for accomplishing left ventriclestimulation may not be ideal. For example, such pacing may result inwide QRS complexes or emboli formation. Thus, endocardial-positionedelectrodes in the left ventricle are avoided. However, electrodes can beplaced on the epicardial surface of the heart through surgicalplacement. The epicardial electrodes are positioned on the free wall ofthe left ventricle and are paced in synchrony with electrodes placednear the septum in the right ventricle.

Since epicardial electrodes require a surgical placement, the patient issubjected to two procedures: percutaneous placement of right ventricleelectrodes (normally performed in a catheter lab by anelectrophysiologist); and surgical placement of epicardial electrodes onthe left ventricle (normally placed by a cardiac surgeon in a surgicalsuite). Such dual procedures are a burden on medical resources and maycarry significant associated extra morbidity and mortality.

Percutaneous procedures have been developed for placement of anelectrode to stimulate the free wall of the left ventricle. In such aprocedure, an electrode lead is advanced through the coronary sinus.Part of the venous system, the coronary sinus extends from the rightatrium and wraps around the heart on or near the epicardial surface andpartially overlies the left ventricle free wall. In this percutaneousprocedure, the electrode remains positioned in the coronary sinusoverlying the left ventricle free wall with the lead passing through thecoronary sinus and through the right atrium to the implantable pulsegenerator.

Unfortunately, a coronary sinus electrode is frequently less thanoptimal. The portion of the free wall most directly influenced by theelectrode is the tissue directly underlying the coronary vein at thelocation of the electrode. For many patients, this may not be thelocation of the free wall that benefits the most from a stimulatingtherapy. Accordingly, the resulting therapy is sub-optimal and it caneven worsen the patient if the asynchrony created by this form ofprevious art biventricular pacing creates more asynchrony than waspreviously present in the patient's heart. Also, some patients may havean extremely small-diameter coronary sinus or the coronary sinus mayhave such a tortuous shape that percutaneous positioning of an electrodewithin the coronary sinus is impossible or very difficult. Notuncommonly, advancing a lead from the right atrium into the coronarysinus is extremely time-consuming. Even if successful, such a procedureconsumes significant health care resources (including precious catheterlab time) including rigorous training of the implanting physicians suchthat a successful implants are only carried out by a small group ofhighly trained highly specialized physicians. This has reduced theavailability of this therapy for patients worldwide. Finally, there arenow up to three leads passing through and occupying the space of thesuperior vena cava (i.e., leads for the electrodes in the rightventricle, right atrium and the coronary sinus). U.S. patent applicationPubl. No. 2005/0125041 published Jun. 9, 2005 shows (in FIG. 1) threeleads passing through a superior vena cava with one lead residing in theright atrium, one in the right ventricle and one passing through thecoronary sinus to the left ventricle.

Attempts at pacing the left ventricle by pacing stimulation in the rightventricle have been suggested. U.S. Pat. No. 6,643,546 B2 to Mathis etal. dated Nov. 4, 2003 describes a lead with an array of electrodesalong its length. The lead is placed in the right atrium and extendedthrough the right ventricle, along the septal wall, and into thepulmonary artery. The concept requires that multiple electrodes from thearray be pulsed simultaneously at significantly high voltages to producean adequate electrical field to stimulate the LV septum. The currentoutput from the pulse generator and battery will be very high due to themultiplicity of electrodes and high pacing voltages. Such high outputwill cause a clinically unacceptable product lifespan and may facilitateelectrode corrosion and/or dissolution issues. Since a large number ofelectrodes and supporting electronics are needed to implement such atherapy delivery mechanism, it is not known yet whether it ispractically feasible, not to mention that it is very complicated both interms of device design/manufacturing as well as clinical practice. Nopublished reports known to this date have demonstrated the functional aswell as clinical benefits for this multiple electrode stimulationapproach in the right ventricle.

As will be described with reference to one embodiment, the presentinvention is directed to a left ventricle pacing system and method whichdoes not require epicardial pacing electrodes or pacing electrodes in acoronary sinus or a coronary vein. As will be described, the presentinvention includes electrodes in the right ventricle near the septalwall. These electrodes create a pulsed electrical field which stimulatesboth the septum and at least a portion of the free wall of the left andright ventricles. The present invention achieves these objectiveswithout requiring excessive energy demands or power consumption.

Generally, the aspects of the present invention are directed to a methodand apparatus for providing right-ventricle stimulation tore-synchronize a contraction of the musculature of the septum and freewall of the left and right ventricles to create coordinated contractionof the septum and free wall. Careful placement of the stimulatingelectrodes in the right ventricle is used to produce synchronouscontractions of the left and right ventricles. In a particular instance,the right ventricle may be captured along with re-synchronization of theleft and right ventricles from a single stimulus point or whilemaintaining the synchrony of the activation and contraction of the leftand right ventricles (in the case that the patient required pacing anddid not have an asynchronous contraction without pacing). Using variousembodiments of the present invention, patients that have an asynchronouscontraction of the heart (either the left or the right ventricles orboth) can be resynchronized.

While not bound by theory, it is believed that resynchronization isachieved using the normal conduction system of the heart, by bypassingthe blocked conduction through XSTIM pacing at the level of the Hisbundle, the contraction achieved in this manner is similar to the normalconduction in the treated heart, reducing or eliminating the possibilityof creating a level of asynchrony that is worse than the level that thepatient had previously.

In one implementation, Xstim biventricular resynchronization facilitatesextension of cardiac resynchronization therapy to patients withrelatively low levels of asynchrony. The improvement in minimum dp/dt(as observed in FIG. 43) during Xstim pacing also suggest that Xstimpacing may also be able to improve patients with diastolic dysfunctionand heart failure (around 50% of all heart failure patients).

In another instance, pacing for patients having bradycardia, tachycardiaor other rhythm management, may be improved by improving upon theasynchronous contraction that often occurs due to the electrical impulseartificially introduced that is not propagating through the normalconduction system of the heart (His-Purkinje system).

Consistent with embodiments and applications of the present invention,an electrode is carefully placed at the His bundle site (“His Pacing”)by screwing in the electrode to get into or beside the bundle itself orby positioning the electrode at a site where the bundle gets to theendocardial surface (denoted supra as EN). Previous His-pacing efforts(to maintain synchronous contractions that would be otherwise lost dueto conventional RV pacing for rate support) have been very burdensomelargely because finding this very small region in the right ventriclehas been very difficult, and the effort is generally time-consuming,expensive and extremely complex even with modern tools and imagingtechniques. Further complicating such procedures is the lack ofknowledge regarding the long-term stability of placing a lead in thislocation. Pacing the distal segment of the His bundle has also beenshown to remove left bundle block (LBBB) in patients with a proximallesion of the bundle. His pacing, however, has been reported to becontraindicated in patients with a distal lesion of the His bundle orwith an intraventricular conduction defect (IVCD), in patients withdiffuse peripheral block (at the distal His or diffuse in the Pukinjefibers), and in patients with advanced HF (NYHA class II to IV) andconduction defects. Accordingly, His pacing is used only in a very smallsubset (<0.01%) of the patients that require ventricular pacing foreither Sick Sinus Syndrome, AV block or other Bradyarrhythmiaindications by an extremely small group of physicians.

It has also been discovered that correct placement of the stimulatingelectrodes along the septum can sometimes allow for re-synchronizationof contractions of left-ventricle myocardium using relatively lowvoltages and may also result in improved QRS width, reducedfractionation, and/or improved timing of a late-activation site in theLV. It has also been discovered that the region in the septum where thiseffect takes place is larger and easier to find when particular methodsare used. One such method includes the use of a waveform herein referredto as a Xstim waveform, where two pulses of opposite polarity areapplied. The Xstim waveform, generally speaking, is the application ofthe two pulses of opposite polarity at the same time, or nearly the sametime, such that both pulses are associated with the same captured (beat)of the heart.

In many patients the pacing region is located near the location wherethe His bundle passes close to the endocardial surface of the rightventricle. But in patients with more diffuse block and heart failure, itmay move down in the septum towards the apex of the right ventricle. Ithas also been discovered that careful selection of the waveform mayallow for effective pacing using lower voltages, thereby simplifying thedesign of the output circuits in the pacemaker and the deliveryelectrodes. It has further been discovered that the desired pacingeffect can also be achieved by a single pulse of sufficient amplitude,usually much higher than the amplitude required by the Xstim waveform,and therefore presenting a much higher risk of diaphragmatic and/orphrenic nerve stimulation. It has further been discovered that theamplitude required to achieve the effect is often lower when that pulseis of anodal nature versus a negative pulse (referenced to the body).

In one embodiment, each electrode may be selectively and independentlyused to stimulate a synchronous contraction. The voltages for eachelectrode are varied to determine the voltage threshold necessary toproduce ventricular capture. In various implementations, discussed inmore detail hereafter, the voltage threshold can be determined usingcriteria other than (or in addition to) whether ventricular capture isproduced (e.g., improved heart function). Low average stimulationvoltage and current may be obtained by selecting the electrode that hasthe lowest effect threshold (effect refers to resynchronization effector to maintaining synchrony of the contraction during pacing effect).

In connection with the various drawing figures and relevant discussions,the following disclosures are incorporated herein by reference in theirentirety: U.S. Pat. No. 6,230,061 B1 to Hartung issued May 8, 2001, fordetails of a cardiac pacemaker with localization of the stimulatingpulses and U.S. Pat. No. 6,907,285 to Denker, et al., dated Jun. 14,2004, for details of a wireless defibrillation system; U.S. patentapplication Publ. No. 2004/0153127 published Aug. 5, 2004 for detailsrelated to the use of a microstimulator in the proximity of at least oneanatomical structure to produce muscular contractions; U.S. Pat. No.6,643,546 B2 to Mathis et al. dated Nov. 4, 2003, for details related tothe treatment of congestive heart failure.

As mentioned above, aspects of the present invention are directed toimproving heart function as indicated by one or more of severalmeasurable characteristics. The discussion and illustrations presentedin connection with FIGS. 21-50 provide examples and related results forone or more of these and other aspects of the present invention. Theseaspects can be implemented in various combinations. To fully appreciatesome of these aspects and the related discoveries, the followingdiscussion of FIGS. 1-20 presents related discussion as well as variousfeatures that are optional to other embodiments, such as thoseillustrated and discussed in connection with FIGS. 21-50.

The present invention may be practiced with currently commerciallyavailable electrode leads and can also be enhanced with speciallydesigned leads. FIG. 1 illustrates the invention in practice with onesuch lead. As is the conventional usage for referencing relativedirection, the terms “left” and “right” are used herein with referenceto the patient's perspective. The terms “upper” and “lower” and similarterms such as “up” or “down” are used with reference to the base B ofthe heart being high and the apex A of the heart H being a lower end.

In connection with various embodiment of the present invention, FIG. 1illustrates approaches for pacing of the right and left ventricles froma lead in the right ventricle in a manner consistent with the abovediscussed aspects. As one such example, with Xstim pacing profiles beingdelivered on electrodes E₁ and E₂, heart function can be improved bypacing and/or mapping to delivering such pulses to a cardiac site. Suchpacing/mapping can also be used to determine a pacing (voltage)threshold, beyond the capture threshold, to improve the heart'sfunction. Such an approach can also be used to provide bi-ventricularpacing from a lead in the right ventricle for such improved heartfunction.

In FIG. 1, a patient's heart H is schematically shown in cross-section.The heart H includes the upper chambers of the right atrium RA and leftatrium LA. The lower chambers are the right ventricle RV and leftventricle LV. Of the various venous vessels opening into the rightatrium RA, only the superior vena cava SVC is shown. Also, of thevarious heart valves, only the mitral valve MV (separating the leftatrium LA from the left ventricle LV) and the tricuspid valve TV(separating the right atrium RA from the right ventricle RV) are shown.The septum S separates the right and left ventricles RV, LV and the freewall FW of the left ventricle LV is separately labeled. The surface ofthe heart wall tissue opposing the chambers is the endocardium and islabeled as EN. The exterior surface of the heart is the epicardium andis labeled EP. Not shown are coronary vessels of the heart or thepericardium surrounding the heart H.

As a specific embodiment, FIG. 1 includes an electrode lead shown ashaving a lead body LB₁ and exposed electrodes E₁ and E₂. The firstelectrode E₁ is positioned near the distal tip of the lead body LB₁. Thesecond electrode E₂ is positioned more proximally on the lead body LB₁.At the distal end, an attachment mechanism AM (such as a passivefixation design with tines or an active fixation design with a metallichelix) is shown for securing the first electrode E₁ to the musculatureof the heart H. The spacing of electrodes E₁, E₂ could be greater orless than that of convention pacing electrodes permitting positioning ofthe first electrode E₁ at the apex of the right ventricle RV and thesecond electrode E₂ in the right ventricle RV near the tricuspid valveTV. However, conventional leads with conventional spacing have been usedwith the first or distal electrode attached to the septum (e.g., by ahelix attachment HA) as shown in FIG. 7A.

According to various embodiments of the present invention, the positionof electrodes E₁ and E₂ is determined by monitoring and analyzing theeffectiveness of the pacing. In one example, an electrocardiogram (ECG)is used to monitor the cardiac waveform. The electrode position may beincrementally adjusted and the feedback from the ECG can be compared foreach position. In a specific example, the QRS width is used in such acomparison. Another parameter that may be considered includes the angleof the vectocardiogram. For example, the analysis of the vectocardiogrammay be viewed in terms of normalization of the vectocardiogram. Forfurther information on vectocardiographic measurements andnormalization, reference can be made to, Sotobata I, Okumura M, IshikawaH, Yamauchi K.; Population distribution of Frank-vectorcardiographicmeasurements of healthy Japanese men. Jpn Circ J. 1975 August;39(8):895-903, which is fully incorporated herein by reference. Inanother example, the efficiency of the contraction can be ascertained bymonitoring the synchrony of the contraction using two-dimensionalechocardiography. In still another example, the efficiency of thecontraction can be ascertained by monitoring the coronary sinuselectrogram to determine the time delay that the activation wave fronthas between the pacing stimuli (or the resulting QRS complex) until aleft ventricular activation is detected at the coronary sinus or anyother (late activation) structure of the left ventricle. This may beaccomplished using an electrophysiology-style catheter or any othercatheter with one or more electrodes close to its tip. In one instance,the goal is to minimize the time delay.

In one embodiment, the lead body LB₁ is flexible and includes abio-compatible, electrically insulating coating surrounding first andsecond conductors C₁, C₂ separately connected to the first and secondelectrodes E₁, E₂. In the various Figures, the lead bodies are broken ata line at the SVC to reveal the internal conductors C₁, C₂ extending toan implantable pulse generator IPG. In fact, the conductors C₁, C₂ arecontained within the material of the lead body LB₁ along their length.The term “implantable pulse generator IPG” is intended to includepacemakers, implantable converter defibrillators (ICD) and cardiacresynchronization therapies (CRT), all known in the art.

The proximal end of the lead body terminates at a pin connector (notshown) as is customary. The pin connector has exposed electricalcontacts uniquely connected to each of the conductors C₁, C₂. The pinconnector may be connected to the pulse generator IPG so as to bereleasable and with the exposed contacts making electrical connectionwith unique contacts of the circuitry of the pulse generator IPG.

It will be appreciated that the prior art contains numerous examples ofcardiac leads for placement in a chamber of the heart where the leadshave, as described above, two or more electrodes spaced along a lengthof the lead, attachment mechanisms such as passive or active fixationand conductors and connector pins as described. The current invention isnot limited to pacing leads only, but rather is equally deployable withprior art ICD leads where it is customary to contain at least twoelectrodes in the RV. Such leads are selected of biocompatible materialand treated (such as sterilized) for chronic placement in the patient.

The implantable pulse generator IPG is a small metallic container sealedfor implantation in the patient and protecting internal circuitry.Commonly, such pulse generators are placed subcutaneously (e.g., in adissected space between the skin and muscle layers of the patient). Forcardiac pacing, such pulse generators are positioned in the upper cheston either the left or right front side of the patient near a shoulder.However, placement need not be so restricted and such pulse generatorscould be placed in any convenient location selected by the physician.

Pulse generators contain internal circuitry for creating electricalimpulses which are applied to the electrodes after the lead is connectedto the pulse generator. Also, such circuitry may include sensing andamplification circuitry so that electrodes E₁, E₂ may be used as sensingelectrodes to sense and have the IPG report on the patient'selectrophysiology.

The lead may be introduced to the vasculature through a small incisionand advanced through the vasculature and into the right atrium RA andright ventricle to the position shown in FIG. 1. Such advancementtypically occurs in an electrophysiology lab where the advancement ofthe lead can be visualized through fluoroscopy.

The pulse generator contains a battery as a power supply. Withsubcutaneous placement, replacement of a battery is possible. However,improvements in battery designs have resulted in longer-lastingbatteries with the benefit of reducing the frequency of batteryreplacement. Alternatively, such batteries may be rechargeable in situ.

The pulse generator circuitry controls the parameters of the signalscoupled to the electrodes E₁, E₂. These parameters can include pulseamplitude, timing, and pulse duration by way of example. The internalcircuitry further includes circuit logic permitting reprogramming of thepulse generator to permit a physician to alter pacing parameters to suitthe need of a particular patient. Such programming can be affected byinputting programming instructions to the pulse generator via wirelesstransmission from an external programmer. Pulse generators commonlyinclude an exposed contact on the exterior of the generator housing.Such pulse generators may also be partially covered with an insulator,such as silicone, with a window formed in the insulator to expose aportion of the metallic housing which functions as a return electrode inso-called unipolar pacing. In bipolar pacing, the window is notnecessary. Most commonly, the electrode is connected by the circuitry ofthe housing to an electrical ground.

While an implantable pulse generator is described in one embodiment, thepulse generator may be external and coupled to the electrodes bypercutaneous leads or wireless transmission. For example, a control ofan implanted electrode is known for phrenic nerve stimulation and isdescribed more fully in a product brochure, “ATROSTIM PHRENIC NERVESTIMULATOR”, AtroTech Oy, P.O. Box 28, FIN-33721, Tampere, Finland (June2004). The Atrostim device sends signals from an external controller toan implanted antenna.

Specific implementations for wirelessly controlled stimulators involvethe use of piezoelectric crystal(s). The crystals can be exited remotely(e.g., with ultrasound) to produce an electrical signal at theelectrode. A number of crystals can be connected in series and/orparallel. In one instance, crystals are connected to ground (e.g., bodycommon) and to generate positive and negative voltages, respectively.The generated voltages can be applied to the electrodes. Suchimplementations can be useful for facilitating placement of theelectrode and crystal and/or for reducing complications (e.g., due tothe existence of a lead body crossing the tricuspid valve).

In one implementation, the crystals are located in the region of His andclose to the left atrium, allowing sensing of atrial activation.Internal circuitry responds to sensed atrial activation to effect theventricular His pacing after a preprogrammed AV delay. This can beparticularly useful for achieving atrial synchronous ventricular pacingwithout an atrial lead.

External pacing devices are typically used for providing temporarypacing therapy. Aspects of the current invention are also believed tohave advantages for this application as critically-ill patientsrequiring emergency, temporary pacing may also suffer further fromasynchronous cardiac contraction associated with conventional RV pacing.If desired, an external unit can be used to test a patient's suitabilityfor the treatment. Patients who benefit from the therapy can thenreceive an implantable pulse generator for longer-term use.

FIG. 2 illustrates a lead body LB₂ in the right ventricle RV with theelectrodes E₁, E₂ directly placed on the septal wall S and held in placeagainst the septal wall through any suitable means. For example, FIG. 2Aillustrates one embodiment for attachment of an electrode against theseptal wall. The lead body LB₂ is shown as having an internal lumen LUwith a port PO near an electrode (e.g., electrode E₂). Any suitableattachment mechanism (such as a pigtail guide wire or an injectedbio-adhesive) can be passed through the lumen LU and port PO to fix theelectrode E₂ in abutment against the septal wall S. Further, a guidecatheter could also be used in moving the implantable lead to assist inthe mapping of the optimal location of the septum.

FIG. 3 illustrates the electrodes E₁, E₂ against the septal wall S butwithout requiring an attachment mechanism. Instead, an intermediateregion (IR) of the lead body LB₃ is formed of shaped memory material(such as nitinol) to assume an S-shaped configuration and urge theelectrodes E₁, E₂ against the septal wall S.

In FIG. 4, the lead body LB₄ has two components LB_(a), LB_(b) joined byan intermediate section IS which may be formed of any elastomericmaterial (such as a shaped memory material). The intermediate section(IS) is biased to urge the two components LB_(a), LB_(b) into collinearalignment. With the intermediate section IS placed against the apex ofthe right ventricle (RV), the bias of the intermediate section IS urgesthe electrodes E₁, E₂ against the septal wall S.

FIG. 5 illustrates the electrodes E₁, E₂ individually placed on theseptal wall S and not retained on a lead body. In such an embodiment,the electrodes E₁, E₂ may be energized in a pacing waveform by wirelesstransmission signals T₁, T₂ from the implantable pulse generator (IPG).Wireless transmission from a controller to an electrode is shown in U.S.Pat. No. 6,907,285 to Denker, et al., dated Jun. 14, 2004.Alternatively, the electrodes E₁, E₂ may be directly imbedded asmicrostimulators into the tissue of the septal wall S as illustrated inFIG. 6. Microstimulators for implantation into human tissue are shown inU.S. patent application Publ. No. 2004/0153127 published Aug. 5, 2004.

In a context similar to that discussed above, FIGS. 1-20 illustrateaspects of the present invention similar to that discussed above inconnection with FIG. 1 where certain of these figures show commoncharacteristics. FIGS. 1, 7B and 8 illustrate example leads and theassociated electrical fields with both electrodes residing within theright ventricle with the distal electrode secured to the apex of theright ventricle, with FIG. 8 showing the ventricles RV, LV and a portionof the lead body LB₁. While such bipolar leads are acceptable for usewith the present invention, a wider spacing between electrodes E₁, E₂can increase the field but can sacrifice some sensing capability. Thistrade-off can be mitigated by use of a three-electrode lead in the rightventricle RV. Such a lead would have a tip electrode and two ringelectrodes, one located near the tip in the RV apex and one in the highpart of the atrium, near the tricuspid valve. The sensing is performedbetween the tip and closer electrode. This will provide good so-called“near field” sensing and avoid so-called “far field” sensing of theatrium or skeletal muscles activity. The pacing could be between thering electrodes to the return electrode located distally to the heart(as will be described). One could also combine the tip and nearest ringas one electrode to the return electrode and the other ring electrode tothe return electrode at the opposite polarity. In a particularembodiment, a ring with a width of 4 mm is separated by a distance of 4mm from a tip with a width of 4 mm.

Another characteristic is the pulse generator IPG which is common toFIGS. 1-7 b. The pulse generator IPG generates a first and a secondpulsed waveform W₁, W₂ applied, respectively, to the first and secondelectrodes E₁, E₂. FIG. 18 shows such waveforms W₁, W₂ of depictingsignals generated by this illustrated IPG. By way of example, and notintended to be limiting, the pulse duration (PD) is between about 0.1 to2.0 milliseconds, the amplitude A may be 0.1 Volts to 10 or 20 Volts andthe time delay TD between pulses is a targeting heart rate (e.g., 50 to200 beats per minute).

The arrangements shown in FIGS. 1-18B show examples of electrodeplacements (e.g., electrode E₁) at various positions along or near theseptal wall. In FIG. 7A, for example, the first electrode E₁ is attachedto the mid- or upper-septum.

The reference electrode RE, used in some but not all such embodiments ofthe present invention, is on the housing of the IPG and positionedsubcutaneously near the right or left shoulder. The re-direction of thefield may also be useful in decreasing defibrillation thresholds forarrangement similar to that shown in FIG. 7B. In FIG. 7B large segmented(for flexibility) electrodes E₂, E₃ are shown in the superior vena cavaSVC near the atrium RA and in the right ventricle to serve as shockingelectrodes to defibrillate a patient.

Another characteristic relating to the above-discussed aspects forimproved heart function concerns placement of the electrodes toeffectively stimulate the septal wall. As an illustrated example of suchplacement, FIG. 9 shows field lines useful for such stimulation andresulting from movement of the electrodes E₁, E₂ from the interior ofthe right ventricle RV (FIGS. 1 and 8) to the septal wall S. Suchmovement shifts the field lines toward both the septal wall S and thefree wall FW of the left ventricle LV.

Certain of the embodiments that use a reference electrode RE incombination with the electrodes E₁, E₂ in the right ventricle, provideeffective pacing of the left and right ventricles LV. Although thephysics and physiology of the mechanism of action are not fullyunderstood, it may be that the reference electrode RE distorts theelectromagnetic field otherwise created between the right ventricleelectrodes E₁, E₂ to urge an intensity of the electromagnetic fielddeeper into the septal wall S of the left ventricle LV. This may be dueto creation of a third high current density spot (or spots) away fromthe two electrodes in the wall and towards the reference electrode atthe point where the current flows between the electrode E₁ and thereference electrode RE and between the electrode E₁ and the referenceelectrode RE while coinciding in space and time. This is illustrated,for example, in FIG. 10. Assuming such a phenomenon occurs, it mayfacilitate the activation of the surviving conduction fibers in the LeftBundle Branch and Right Bundle Branch of His and Purkinje fibers andcreate a more rapid and uniform activation of the left and rightventricles that follows a similar pattern to the normal activationpresent in patients without conduction defects.

The reference electrode may be physically attached to the housing of theimplantable pulse generator IPG (and thereby having a neutral charge).Such an electrode RE is shown in FIGS. 1-7B. It will be appreciated thatthe reference electrode RE can be connected to the implantable pulsegenerator IPG by a conductor. The reference electrode could be anothercommon electrode that exists in the conventional pacing or ICD system,such as an electrode in the atrium or a defibrillation coil electrodesituated in the SVC, RA or RV.

As shown in FIG. 10, the consequence of the reference electrode RE mayhave a deforming effect on the electromagnetic field generated betweenthe first and second electrodes E₁, E₂. This is illustrated in FIG. 10by distorting the left field lines LFL toward the septal wall S and freewall FW of the left ventricle LV. Also, the right field lined (RFL) arecompressed toward the axis FA to alter the field from the symmetricpresentation of FIGS. 8 and 9 to the asymmetric presentation of FIG. 10with the field biased toward the septal wall S and the free wall FW ofthe left ventricle LV.

It has also been found that within energy levels associated withavailable implantable pulse generators (in some instances up to 10 or 20volts), effective activation of the left and right ventricles LV can beachieved with appropriate placement of the pacing leads.

Chronic pacing with an anodal electrode has been reported to create anexit (anodal) block, meaning that the capture thresholds of the cardiactissue may go beyond the voltage range of the pulse generator. When thishappens the beneficial effect of the stimulation is lost. Since capturecan be lost, the patient's life may be placed at risk by such an event(e.g., in the case of a third degree AV block patient).

According to one embodiment of the present invention, the polarity ofthe charged pulses seen at electrodes E₁ and E₂ may be alternated. Thiscan be particularly useful for avoidance of anodal blocking (gradualrising of the threshold voltage necessary to capture and re-synchronizethe myocardium). Such polarity swapping may be implemented using asuitable periodicity. In a particular example, the polarity of theelectrodes is switched after several hours of operation. In anotherexample, this polarity is alternated beat by beat, so that the netcharge delivered to the tissue over two beats would be zero (assumingreversible reactions took place at the electrode tissue interface). Thefrequency of alternation could be varied in a very wide range and stillaccomplish the goal of balancing the charge delivered, to allow for thenet charge delivered on average to be near zero. This can be useful foravoiding the issue of anodal block and minimizing the risk of electrodedissolution and/or corrosion.

It has been discovered that in some instances proper placement of thelead along the septum produces unexpectedly small QRS widths. Moreover,proper placement may also result in lower voltage thresholds. Theoptimal lead location can be determined with the assistance of thesurface ECG parameters (e.g., QRS width and/or activation vectors).

The positioning of the reference electrode RE may be directly on thehousing of the implantable pulse generator IPG or may be separate fromthe internal pulse generator as previously mentioned. In one instance,the reference electrode RE can be placed in the left ventricle (FIG. 11)(or in the tissue of the free wall FW as shown in phantom lines in FIG.11), on the epicardial surface EP (FIG. 12) or in the coronary sinus CS(FIG. 13).

Positioning the reference electrode RE relative to the heart can affectthe distortion of the field in the area of the left ventricle free wallFW subject to pacing. Particularly for a subcutaneously placed referenceelectrode (which is preferred to minimize the invasive nature of theprocedure), the electrical conduction path from the right ventricle RVto the reference electrode will vary considerably between patients.

Also, the direction of field distortion may alter the region of the leftventricle LV subject to pacing. For example, FIG. 15 illustrates thereference electrode RE₁ placed high relative to the heart, resulting ina distortion of the field toward the upper end of the left ventricleseptum and free wall FW. FIG. 16 illustrates placement of a referenceelectrode RE₂ lower relative to the heart and to deflect the intensityof the field toward the lower end of the left ventricle septum and freewall FW.

While the reference electrode could be a single electrode, multipleelectrodes could be provided for subcutaneous placement and eachconnected by a switch circuitry SW of the implantable pulse generator asillustrated in FIGS. 15 and 16. The patient's response can be noted witheach of the several reference electrodes RE₁, RE₂ separately connectedto the ground or housing of the implantable pulse generator. The patientcan then be treated with the electrode showing the most effectivenessfor the particular patient. Further, over time, a patient's response maychange and the implantable pulse generator can be reprogrammed to selectany one of the other reference electrodes as the switched electrode.

In addition, the catheter LB₅ within the right ventricle can havemultiple electrodes along its length (as shown in FIG. 7). Individualpairs of these electrodes E₁-E₄ can be switched on or off over time sothat the appropriate pair of electrodes within the right ventricle isselected for optimized left ventricular pacing.

FIG. 14 illustrates how the field can also be distorted by dielectricmaterial DM placed on a side of the electrodes E₁, E₂ opposite theseptal wall S. The dielectric material DM result in a distortion of theelectrical field biasing the left field lines LFL toward the septal wallS and the free wall FW. Of course, this configuration will work evenbetter with a reference electrode which will enhance the benefit.

While positioning of the electrodes E₁, E₂ within the volume of theright ventricle RV is effective in combination with a referenceelectrode RE (FIG. 10), movement of the electrodes E₁, E₂ directlyagainst the septal wall S may further enhance the therapeutic benefit ofthe present invention for reasons described above. Various techniquesfor movement of the electrodes E₁, E₂ against the septal wall S aredisclosed.

In various embodiments, the reference electrode is grounded to thehousing of the implantable pulse generator. FIG. 17 illustrates analternative embodiment where the reference electrode includes two activeelectrodes AE₁, AE₂ external to the heart. The active electrodes AE₁,AE₂ are paced with pulsed waveforms which are polar opposites of thewaveforms on electrodes E₁, E. This creates dual uni-polar field inaddition to the left field lines LFL previously described.

In the Figure, the amplitude of the waveforms from FIG. 18 (or otherwaveforms as described) is shown in phantom lines as the battery voltageapplied to the four poles on the left of FIG. 19 to charge the twopacing capacitors C₁ and C₂. Details of the charging circuitry as wellas other controlling circuitry for pacing and sensing are omitted forease of illustration. In one instance only capacitor C₁ is charged forthe pacing output, whereas C₂ is not charged. Capacitor C₃ and C₄ areoptionally implemented for coupling the pacing output to the patient.For ease of illustration and explanation, the output waveform from FIG.18 with the same amplitude and simultaneous timing is assumed for thedesign schematic in FIG. 19. A switch S₁ permits selection betweenunipolar pacing and pacing Xstim or similar pacing (by contact withswitch pole A₁) or bi-polar pacing (by contact with switch pole A₂).Selection between bi-polar pacing or Xstim pacing is made by applying adigital signal with the timing information as shown in FIG. 18 to eitherT₁ or T₁ and T₂, namely to either toggle the switch S₅ or S₂ and S₅simultaneously. An AND gate is used to allow the close of the switch S₂only for pacing according to Xstim. Switches S₃ and S₄ permitre-neutralization of the pacing charges at the patient-electrodeinterface.

As is customary with implantable pulse generators, the device may beprogrammable to achieve either conventional bipolar or unipolarstimulation or to achieve the Xstim stimulation through an externalprogrammer or controlled automatically by the device. The selection canbe based on user preference or be driven by physiological factors suchas widths of the patient's QRS complex or the conduction intervalbetween the stimulus to a far away region in the heart. In addition,switching between the Xstim pacing and other pacing can also bedetermined by the percentage of pacing with a preference for a higherpercentage with the pacing of the present invention. Further, theswitching from a first type of pacing to the Xstim pacing can be usedwhen there exists an exit block or the pacing electrode is located ininfarcted myocardium when first type pacing does not capture (effect thedepolarization of) the myocardium at the high output level. Theautomatic determination can be effected through the deployment of anyautomatic capture detection technology including, but not limited to,electrical sensing of the heart. Additionally, wireless network-enabledswitching function for therapy optimization can also be implemented withthe present invention. In such cases, certain patient physiologic dataare gathered by the implantable device and sent to a remoteserver/monitor through a wireless communication network.

In connection with other embodiments and related to the waveforms shownin FIG. 18, the stimulus voltage is consistent with discharge of an RCcircuit as shown by FIG. 23A. This may be accomplished by connecting theelectrode(s) to the anode (and/or cathode) of a charged capacitor.

According to another embodiment of the present invention, the stimulusvoltage is consistent with the discharge of two sets of two capacitorsin succession, as shown by FIG. 23B. This may be accomplished byconnecting the electrode(s) to the anode (and/or cathode) of a firstcharged capacitor and then to a second charged capacitor. Thisembodiment may be useful for reducing the voltage swing of the pulse,thereby altering the delivery of energy during the active stimulationperiod and potentially minimizing the voltage required to achieve thedesired effect. In a particular instance, a first set of capacitorscould be connected to electrode E₁ and a second set could be connectedto electrode E₂. The voltages provided to the electrodes could be ofopposite polarity as in the standard Xstim waveform or could bealternated as described above to make the net charge delivered to theelectrodes equal to zero.

Other embodiments may allow for the use of two sets of three or morecapacitors as shown by FIG. 23C. Moreover, various voltage-regulationtechniques may be used to provide a constant voltage, or squarewaveform, as shown by FIG. 23D. This may be useful to provide a moreconstant delivery of voltage during the active stimulation period. Insome instances, such waveforms may allow the reduction of voltagethresholds required to achieve the desired effect. According to oneembodiment of the invention, one of these groups of three or morecapacitors could be connected to electrode E₁ and the other group ofthree capacitors could be connected to electrode E₂. The two groups maybe charged to opposite polarities, as in the standard Xstim waveform.Alternatively, the groups may alternate between electrodes E₁ and E₂, asdescribed above, resulting in the net charge delivered to the stimuluspoint by the electrodes equal to zero.

Furthermore, in a less expensive device, using a single capacitorelement (or multiple capacitors arranged in parallel), a single set oftwo capacitors independently addressable or set of three or morecapacitors each independently addressable, the same effect could beachieved by using an anodal pulse delivered through the capacitivedischarge of one, two or three or more capacitors to one of theelectrodes with a larger amplitude voltage. This anodal pulse will bealternatively connected to one of the stimulating electrodes in one beatand to the next electrode on the next beat. In still another device thealternating frequency could be lower. For example, the anodal capacitivedischarge could be alternatively connected to electrode E₁ and then toE₂ every 2 to 10,000 beats. If the alternating charges are equallydistributed, the net charge delivered may be kept very close to zero.During the implantation of such a device the physician may place anintraventricular pacing lead in a preferred location (locus) thatmaintains the effect (using one of the previously-described methods,making each electrode alternatively the anode) when either of theelectrodes is the anodal electrode.

The pulse width of the various embodiments may be varied according tothe desired treatment and/or in accordance with the response of theparticular patient. Example pulse widths may range from 0.05 ms to 5.0ms.

According to certain example embodiments of the present invention,resynchronization is achieved by presenting a pulsing signal (waveform)to a sweet spot (e.g., locus in the septal part of the RV endocardium)and, every so often, modulating the signal such as by changing itspolarity. In such embodiments where both an anode and cathode are usedto present the pulsing signal, one manner of modulating the signal is byreversing the polarities of the signal relative to the anode andcathode. Where the pulsing signal is presented by an electrode and areference voltage (e.g., a node at the can and/or at the body undertreatment), the signal can be modulated in a similar manner by addingand/or skipping pulses.

As discussed infra, the power consumption of the pacing device can be animportant consideration. While not bounded by theory, it is believedthat different pacing profiles can be particularly advantageous tocontrolling pacing power. For example, during times that the pulsesapplied to each electrode overlap, the effective voltage seen betweenthe electrodes is believed to be equal to that sum of their amplitudes.

In another embodiment, the pulses shown by the figures are applied tothe ring and tip electrodes, such as those illustrated in FIG. 22. Thepolarity of the voltages, as relative to each other and/or a referencevoltage, may be alternated periodically (e.g., beat by beat or every Npulses). As discussed above, such alternating may be particularly usefulfor mitigating anodal blocking. Moreover, alternating of pulses may alsomitigate corrosion of the electrodes.

Referring back to FIG. 18, such pulses are shown as square waveformsbut, in practice, can be any of various geometries. With reference toFIG. 18 and the earlier figures, the first electrode E₁ has positivelycharged pulses only. The second electrode E₂ has negatively chargedpulses timed to coincide with the positively charged pulses of thepositive electrode E₁. While direct current (DC) pulses are preferred,the electrodes E₁, E₂ could be energized with alternating current pulseswith the signals to the electrodes E₁, E₂ out of phase such that thepositive pulses on the first electrode E₁ coincide with negative pulseson the second electrode E₂ and negative pulses on the first electrode E₁coincide with positive pulses on the second electrode E₂.

With the electrodes E₁, E₂ charged with opposite pulses, it isApplicants' current understanding that an electrical field is createdbetween the electrodes E₁, E₂ with a field axis FA (FIG. 8) extending ina line between the electrodes E₁, E₂. In the absence of distortinginfluences (such as external magnetic fields, external electrodes ornon-homogonous conductivity due to variances in conductivity of blood,tissue bone, etc.), the field is symmetrical about the field axis FA andis represented by field lines illustrated in the drawings as left fieldlines LFL to the left of the axis FA (with left being from the patient'sperspective) and right field lines RFL. The field lines represent theintensity of the electrical field. The intensity diminishes rapidly as afunction of the distance from the field axis FA.

As discussed above in connection with various embodiments including theelectrodes E₁, E₂, in order for the fields generated by the electrodesE₁, E₂ to have a significant influence on both the septal walls and thefree wall FW of the left ventricle LV, a voltage potential across theelectrodes is set at a substantially high level. However, such highvoltages are not practical in a pacing electrode and are more normallyassociated with defibrillating treatments. Also, such voltages may causephrenic nerve and/or diaphragmatic stimulation and may also cause asignificant drain on a battery that would require impractical frequencyof battery replacement.

FIG. 18 illustrates an example waveform with electrodes E₁, E₂ beingsimultaneously pulsed with opposite polarity. FIG. 18A illustrateswaveforms W₁′, W₂′ of similar structure to the waveforms of FIG. 18 butout of phase. The first set of pulse illustrated in waveforms W₁′, W₂′present a partial overlap duration OD (OD is a positive value). Thesecond set of pulses are further out of phase such that the beginning ofone pulse coincides with the end of another pulse (OD=0). The third setof pulses includes pulses that are out of phase such that the leadingedge of one pulse occurs after the end of the first pulse of the set (ODhas a negative value). With FIG. 18A at least a portion of time includesa monopolar pacing from individual ones of the electrodes E₁, E₂ to thereference electrode RE. This pacing creates out of phase monopolarfields F₁, F₂ as illustrated in FIG. 18B. Values of OD can range fromthe entire pulse length (e.g., around two milliseconds) to a negativevalue of several milliseconds (e.g., around negative two milliseconds).Although not explicitly shown in FIG. 18A, either of the negative orpositive pulses can lead the other pulse, respectively. Also, while theamplitudes of the two waveforms are shown to be equal, they need not beequal in practice nor do they necessary need be implemented as strictsquare waves. For non-square wave pulses or pulses with relatively slowfall or rise times, the OD can be calculated accordingly. In oneexample, the OD may be calculated from beginning or end of the rise/fallof each pulse, respectively. In another example, the OD may becalculated from when each pulse reaches a certain voltage level,respectively, or once the pulse has maintained a certain voltage levelfor a period of time.

FIG. 19 illustrates a representative circuit in schematic format for aportion of a cardiac stimulation pulse generator that is capable ofproviding pacing output for either the conventional waveforms or Xstimwaveforms as herein. The circuit of FIG. 19 could be for an implantablepacemaker or any external stimulation system for diagnostic ortherapeutic use.

The stimulation device has three output terminals that are connected tothree electrodes E₁, E₂, RE in the body. Electrodes E₁, E₂ arepositioned in the right ventricle RV with it being preferred that atleast one of these electrodes be in direct contact with the septum S.

The reference electrode RE is an indifferent electrode which can beconnected electronically to the housing of the implantable pulsegenerator IPG. The reference electrode RE may be an electrode directlyon the implantable pulse generator or any other electrode for placementinside or outside of the heart as described above.

The present invention can also be extended to the defibrillation therapywhere high-energy pulses with various waveforms are delivered throughelectrode systems to treat tachycardia and fibrillation (both atrium andventricle). The present invention is believed to be able to achieve alower defibrillation threshold due to better distribution of theelectrical field, causing higher voltage gradient at least in certainparts of the heart compared to that by the conventional defibrillationconfiguration as seen in FIG. 7B. Additionally, the present inventioncan be used to perform anti-tachy pacing where faster than conventionalpacing pulse sequences are used to stop certain tachyarrhythmia. Aspectsconsistent with present invention are believed to provide wider coverageof the electrical field and the capability of capturing specialconduction systems in the heart (both atrium and ventricle).

In a particular embodiment, the electrodes E₁ and E₂ are positionedproximate to one another as shown in FIG. 22. This can be particularlyuseful for localizing the region in which the electrical stimulus (usingone of the configurations described before) can achieve the desiredsynchronization or resynchronization effect. For example, the electrodesmay have a width of around 4 mm and may be positioned within a distanceD of about 5 mm from one another. In another example, the electrodes maybe positioned within a distance D of about 2 mm or less.

The selective placement may be modified for a particular dysfunctionand/or for a particular patient. For instance, the electrodes may bepositioned near the His bundle. Locating the electrodes near the Hisbundle may advantageously allow for capture of both the right and leftventricle. Moreover, resynchronization of the left (or right) ventriclemay be possible even for cases of LBBB (or RBBB).

FIG. 21 shows a system for selectively placing the electrodes. In aspecific embodiment the lead discussed in connection with FIG. 22 may beused. The lead position is adjusted through various methods viaconceptual block 104. If desired, the lead position may be monitored andlocation information may be provided to myocardium capture analysisblock 102. Myocardium capture monitor block 106 monitors theeffectiveness of the current lead position in capturing andre-synchronizing a contraction of the myocardium of the left and rightventricles. The monitor information is provided to myocardium captureanalysis block 102, which processes the received information for thepurposes of positioning the electrodes.

In a specific example, monitor block 106 uses ECG measurements tomonitor myocardium capture and re-synchronization. Analysis block 102may analyze various factors of the far field measurements including, butnot limited to, the QRS width (e.g., determined from a vectocardiogram).The ECG measurements may be supplied from a number of different inputsincluding, but not limited to, defibrillation coils, the can of theimplantable device, an electrode of a pacing or sensing lead or anexternal ECG (or similar) device.

In another example, monitor block 106 may measure the amount of bloodflow resulting from a contraction of the myocardium.

The system of FIG. 21 may also be used to adjust otherre-synchronization parameters. For instance, the voltage levels andwaveforms may be adjusted according to feedback from monitor block 106and analysis from analysis block 102. In particular it has beendiscovered that careful placement may allow for low voltages to beapplied to the electrodes. In one embodiment, the pacing impedance ofthe lead and electrodes is low to allow for effective delivery of thepacing voltage. This may be useful for reducing the power consumption ofthe device and for reducing the voltages necessary to deliver thestimulus. By proceeding in this manner, (e.g., using low impedance andmaintaining low voltage), phrenic nerve stimulation or diaphragmaticstimulation, both highly undesirable side effects of high pacing, may beavoided.

In a particular embodiment, the lead has a screw with a short screwrelative to screws used to reach the left ventricle or the His bundle.This allows for fixation of the lead until encapsulation and helpsreduce mechanical problems associated with such attachments. In oneinstance, the screw may be made from a non-conductive material, therebyelectrically isolating the attachment point. In another instance, thescrew may be otherwise electrically isolated from the electrodes fordelivering the pacing voltage even where the screw is made from aconductive material.

In another embodiment, a hook is used as the attachment mechanism. Yetanother embodiment includes the use of a T-bar as the attachmentmechanism.

Due to these and other aspects, one of skill in the art would recognizethat the use of the reference electrode, as discussed herein, may beoptionally implemented to provide effective re-synchronization. In onesuch instance, the reference electrode is used to provide a referencevoltage derived from the in vivo voltage at a particular location. Thisreference may be used to reference the voltage provided at the stimuluslocation to the particular location. For example, the reference locationmay be taken at the can location or from a reference electrode locatednear the stimulus location. In another instance, no reference electrodeis used.

It has been discovered that selective placement of the electrodes mayprovide a number of unexpected advantages. More specifically, selectiveplacement of the electrodes along the septum appears to providere-synchronization of the left and right ventricles even for cases ofLBBB where the lesion of the bundle would not be considered proximal.Furthermore, in many instances a large improvement has been seen in thelevel of synchrony in patients with LBBB and also in patients withmoderate or advance HF and conductions defects including LBBB, RBBB andIVCD. For instance, locating the electrodes near an optimal location onthe septum has been shown to produce smaller than expected QRS widths.Moreover, the threshold voltages necessary to capture the myocardium ofthe left and right ventricles or to produce the smaller than expectedQRS widths (or indications of improved heart function) may be relativelysmall.

FIG. 24 shows an example of a sheath for use within the right ventricle166 of the heart. The outer sheath 156 is designed to be insertedthrough the mitral valve 158 and into ventricle 166. Outer sheath 156may include a J-type bend as shown in the figure. In variousapplications, this advantageously facilitates the placement ofelectrodes 160, 164 near the septum and/or the tricuspid valve 162. Inone embodiment, one or more of the outer and an inner sheath 154 mayarranged to allow directional control of the sheath position (e.g., byallowing for the adjustment of their curvature). The inner sheath and/orthe outer sheath may have an electrode located at their tip to use forpace mapping the locus (e.g., following procedures in FIG. 45). This canbe useful for facilitating the insertion of the chronic pacing lead. Theinner and out sheaths may be peelable so that the pacemaker lead is keptin place while the sheaths are removed.

In a specific embodiment, inner sheath 154 is located within outersheath 156. Inner sheath 154 may be adjusted, relative to outer sheath156, using adjustment mechanism 152. In one instance, the adjustmentmechanism 152 includes an adjustable track wheel or another similarmechanism. Additionally, inner sheath 154 may contain a pacing leadand/or a guide wire for additional stability. The adjustment of innersheath 154 may be accomplished through a number of different techniques.According to one such technique, the inner sheath is allowed freedom toadvance through the outer sheath and to move along the septum. Inanother example technique, the inner sheath may be arranged to directthe lead placement (e.g., by allowing for the adjustment of itscurvature).

External pacing device 150 provides electrical pulses to the electrodes160, 164. The positioning of the electrodes 160, 164 may be adjusted andthe effectiveness of each position may be monitored. Various examples ofsuitable monitoring techniques are discussed in more detail herein. Insome variations, the adjustment mechanism includes a number of fixedsettings that can be reproduced. This allows for easily retrievablepositioning of the electrodes 160, 164 as correlated to theeffectiveness of each position. For example, the inner sheath may beadvanced along positional settings 1 through 10 and correspondingmonitoring input may be used to determine which setting is preferred.The inner sheath may then be set to the preferred setting after acomparison between the results corresponding to each of the testedsettings.

In one embodiment, each electrode may be selectively and independentlyused to stimulate a synchronous contraction. The voltages for eachelectrode are varied to determine voltage threshold necessary to produceventricular capture or to produce improved heart function. Low averagestimulation voltage and current may be obtained by selecting theelectrode that has the lowest effect threshold (effect refers toresynchronization effect or to maintaining synchrony of the contractionduring pacing effect).

In one embodiment, the outer and inner sheaths may then be removed. Anumber of techniques may be used for such a removal. Using one suchtechnique a guide wire is advanced through the sheaths and is used tohold the pacing lead in place while the sheaths are removed. In anothertechnique, the sheaths are constructed with a slit that allows for theirremoval from the pacing lead without significant force being applied tothe pacing lead.

In one embodiment, the inner sheath may function as a temporary pacingdevice connected to an external pacing source (e.g., using an electrodelocated at the tip of the inner sheath). The external pacing source mayadvantageously be equipped with additional processing and displaycapabilities (relative to an implantable device, which is often limiteddue to battery life and physical size constraints) to assist in locatingthe proper placement location. The inner and outer sheaths may beremoved once the pacing lead is attached. The pacing lead may also beconnected to an implantable device.

In one implementation an electrode may be placed on the outer sheath andthe inner sheath is not utilized at all. In other implementations, ashaped sheath is used with an electrode in the tip for pace mapping. Theshape of the sheath can be designed to mimic the particular patient'sshape of the access trajectory from the superior vena cave, to theregion of the His bundle, potentially alleviating the need for asteerable sheath.

In a specific instance, the external device operates to provide avariety of different voltage waveforms and/or stimulus timings to thestimulus location. Feedback from an ECG or other device may be used toidentify the preferred waveforms. The implantable device may then beuploaded with corresponding information for use in providing stimulus.In one such instance, the pacemaker may include a wireless port thatallows an external interface to monitor and/or adjust the pacingfunctions. In this manner, the external device need not provide thestimulus through the external sheath. Instead, the implantable devicemay deliver the same set of stimulus using the wireless interface.

In another instance, the outer sheath may be designed with a removableinterface that is compatible with both the external pacing device andthe implantable pacing device. This allows for the use of the externalpacing device during placement of the electrode(s) and use of the sameouter sheath with the implantable pacing. This may be particularlyuseful for reducing the size of the sheath, the cost of the device orfor simplifying the procedure by avoiding the step of removing the outersheath.

In connection with the various drawing figures and relevant discussions,the following disclosures are incorporated herein by reference in theirentirety: U.S. Pat. No. 6,230,061 B1 to Hartung issued May 8, 2001, fordetails of a cardiac pacemaker with localization of the stimulatingpulses and U.S. Pat. No. 6,907,285 to Denker, et al., dated Jun. 14,2004, for details of a wireless defibrillation system; U.S. patentapplication Publ. No. 2004/0153127 published Aug. 5, 2004 for detailsrelated to the use of a microstimulator in the proximity of at least oneanatomical structure to produce muscular contractions; U.S. Pat. No.6,643,546 B2 to Mathis et al. dated Nov. 4, 2003, for details related tothe treatment of congestive heart failure.

Consistent with these and other example embodiments of the presentinvention, FIGS. 24A-D depict additional waveform patterns that may beprovided by an electronic circuit. For example, FIG. 24A shows pulsesA1, A2 and A5, which represent voltages applied to a first electrode(e.g., the voltage differential between the tip and the can), whilepulses A3 and A4 represent voltages applied to a second electrode (e.g.,the voltage differential between the ring and the can). Control logic inthe pacemaker device allows for the individual adjustment of the voltageamplitude of the various pulses and for the adjustment of the pulsewidth or duration. The specific parameters may be implemented byiteratively changing the waveforms and monitoring the effectiveness ofthe pulse. For instance, the selection of the ideal waveform may be madeby selecting the waveform that produces the smallest QRS width asmeasured by an ECG. While FIG. 24A depicts the pulse polarity asalternating each beat, it should be apparent from the discussion hereinand from FIGS. 24B-C that this is merely one example of a possible pulsemodulation scheme.

In a particular embodiment, one or more pulses may be withheld as shownby the lack of a pulse on the ring electrode that corresponds to pulseA5 on the tip. In this sense the ring electrode pulse has effectivelybeen withheld or skipped. In certain embodiments, either or both of thepulses may be withheld. Such withholding of pulses may be periodicallyimplemented (e.g., once per every N pulses, or once every 20 minutes per24 hours to allow heart to be conditioned by its own intrinsiccontraction if the intrinsic heart rate is above a certain acceptablerate, such as 50 beats/minute). In another instance, the withholding maybe responsive to feedback from a sensing electrode or ECG input.

It has been reported in literature that a small percentage ofconventional RV apical pacing, which has been shown to be detrimental tothe cardiac function, provided benefits to the overall patient wellbeingdue to the healthy sympathetic and parasympathetic exercises introducedby the sporadic cardiac stress associated with RV pacing. As the pacingdisclosed herein (including Xstim pacing) has been shown toresynchronize the LV ventricle, reducing the stress level of thediseased hearts, the withholding of (Xstim) pacing signals periodicallyor sporadically is useful to improve the overall patient wellbeing.

These and other advantages are supported by the experimental resultspresented in FIGS. 25-45 and the related descriptions. While theinvention is not limited to any specific advantages, the variousresults, advantages and other data provide support for the variousembodiments disclosed herein.

As discussed herein in connection with various aspects of themethodology useful for implementing the present invention, an exampleprocedure for determining placement of a lead for pacing involves atleast one repetition of pacing, sensing and repositioning using at leastone lead adapted to deliver a pacing profile. While, not all of the datashown in the various figures was implemented as part of the experimentaltests discussed herein, it is believed that the data shown is accurate.In a specific implementation of this procedure, pacing of the heart isaccomplished using a lead placed in the right ventricle and near the Hisbundle. For example, the lead can include two electrodes (and in someinstances one) to deliver oppositely charged pulses. Heart functionalityassociated with the pacing then is monitored. The monitoring can includeone or more of the following examples, ECG readings (e.g., QRS width orfractionation), electrical activity of a late activation site in theleft ventricle, mechanical contraction of the heart or measurement ofthe blood flow (e.g., the rate of change in pressure). The lead isrepositioned and pacing and monitoring can be repeated.

Once a desired lead placement has been selected, pacing can beimplemented in various ways. For instance, DDD (dual chamber) pacing canbe implemented with or without a low atrial rate (e.g., around 50 beatsper minute) and an AV delay of around one-half of the baseline orintrinsic AV interval. The DDD pacing can also be modified to use avariety of different Xstim pacing profiles, non-Xstim pacing profilesand combinations thereof.

Also according to an embodiment of the present invention, a way toassess improved heart function involves determining placement of a leadfor sensing a late activation site in the left ventricle. The lead,which is capable of sensing electrical activity in nearby heart tissue,is advanced through the CS (coronary sinus) until monitoring resultsfrom the lead represent activation of a late activating region. The leadcan be continuously advanced until activation of a distal electrode onthe lead no longer occurs before any other electrode(s) on the lead. Atthis point, the current lead position can either be maintained or thelead can be slightly retracted.

FIG. 25 shows a comparison of baseline activity to Xstim activity asmeasured by an ECG. Generally speaking, FIG. 25 shows a 12 lead ECGrecordings for a patient with a pacing lead placed according to themethodology described in connection with FIG. 45. The right side showsintrinsic/baseline activity when Xstim pacing of the patient is stopped.The left side shows the effect that pacing generated by Xstim pulses hason the 12 lead ECG of the patient.

The portions of the waveforms 2502 represent the narrow and lessfractionated 12 lead surface ECG results that occur in response to Xstimcaptured beats of the heart. The portions of the waveforms 2504represent some of the wide and more fractionated 12 lead surface ECGthat occur during baseline intrinsic heart electrical activity of thesepatients and is indicative of poor heart function relative to Xstimpacing.

FIG. 26 shows a comparison of baseline activity to Xstim activity asmeasured by a 12 lead surface ECG. The comparison of waveforms 2601 to2602 represents an improvement in the width of the QRS complex.Specifically 2602 show a wide QRS complex corresponding to intrinsicpatient activity. 2601 shows a respectively narrow QRS complexcorresponding to capture/pacing using Xstim. 2603 and 2604 show thedecrease in fractionation due to capture/pacing using Xstim. 2604 showsthe intrinsic fractionated pulse, whereas 2603 shows the improved pulsedue to Xstim pacing.

FIG. 27 shows a comparison of baseline activity to Xstim activity asmeasured by a 12 lead surface ECG. FIG. 27 shows measurements taken fromLV1 and the ECG (lead III and AVR). LV1 represents readings taken fromthe CS lead. The CS lead is positioned near the latest activating regionof the left ventricle (accessed through the great cardiac vein). In thiscase, the waveform of LV1 represents activation of the posterior lateralwall close to the base of the left ventricle.

Waveforms 2701 and 2702 correspond to Xstim pacing. First activation2701 represents activation of the left atrium. The next activation 2702represents activation of the left ventricle at the posterior lateralbasal region. 2703, 2704 and 2705 correspond to intrinsic heartfunction. 2703 and 2704, respectively, show the atrial and leftventricular activation during baseline (no Xstim) pacing. The atrialsensed activity represents activation of the left atrial mass that lieson top of the great cardiac vein where the LV1 electrode is located andthe left ventricle sensed activity represents the activation of thebasal section of the posterior lateral wall of the left ventricle. 2705shows, in conjunction with 2704, the activity of the left ventricleoccurring at the end of the QRS complex or very late in the activationcycle during baseline activity of the heart (no Xstim pacing). 2706, inconjunction with 2702, shows the activation moved to the first half ofthe QRS complex during Xstim pacing.

FIG. 28 shows comparisons of Xstim pacing and intrinsic pacing. Theupper graph shows results from a plurality of patients. A set of twocolumns is provided for each patient. The first column of each set showsthe baseline QRS width (i.e., without Xstim). The second column of eachset shows with Xstim pacing. As apparent from the graph, Xstim pacingshows a decrease QRS width for nearly all patients. For patients whomexhibit an already narrow QRS (and thus are expected to have normalconduction of the activation wave in the ventricles), further narrowingof QRS width is neither expected nor necessarily desirable. In thefigure it can be observed that the change in QRS width in these patientsis not as pronounced and can even be expected to widen the QRS in somecases. However, the overall QRS width is still narrow in general andsuggests that Xstim provides near normal electrical conductionproperties.

The second, lower graph shows the Xstim voltage amplitudes versus theQRS width for the average between the patients (not all patients havedata points at all voltages). As can be seen from the graph, the Xstimpacing reduces the QRS width. Moreover, as the voltage of the Xstimpacing increases the average QRS width reduction also increases. Whilenot bounded by theory, the relationship between the average QRS widthand the voltage of the Xstim pacing may be related, in part, to patientsexhibiting different threshold voltages necessary to produce the reducedQRS width. This suggests that, contrary to prior teachings, criteriaother than the capture threshold can be used to determine the pacingvoltage.

FIG. 29 shows respective sets of baseline and Xstim pacing results forthe CS activation time. For the upper graph the first bar in each setshows CS activation time for the baseline (i.e., no Xstim pacing) andthe second bar shows the CS activation time for Xstim. Time is measuredfrom the Q of the QRS complex wave to LV1 activation, where LV1corresponds to 2704 or 2702 and Q activation corresponds to 2707 (FIG.27). The lower graph shows the CS activation time versus the Xstim pulseamplitude. The first bar represents the baseline without any Xstimpulses.

FIG. 30 shows the measurements of asynchrony obtained via echo imagingof a plurality of patients (patient 6 has no recordings) with respect toa baseline and Xstim pacing. Tissue Doppler imaging (TDI) was used tomeasure the average difference of the mechanical activation time of thebasal septum, basal lateral wall and basal posterior wall. The graphrepresents the average of the absolute value of the difference betweenthe three activation times as represented by the formula {|(posteriorwall−lateral wall)|+|(septum−lateral wall)|+|(septum−posteriorwall)|}/3. Each value represents the respective time of activation ofthe basal septum, the basal lateral wall or the basal posterior wall.The mechanical activation times are determined based upon echo imaging(TDI). Where the asynchrony is high the graph shows a significantdecrease in asynchronous activity; however, where the asynchronousactivity is close to normal, the use of Xstim pacing may notsignificantly decrease asynchronous activity and may even increaseasynchronous activity slightly. These relatively normal patients arestill able to be paced with relatively synchronous activity using Xstimpacing at the optimal site, when compared to other forms of pacing.

FIGS. 31A and 31B show a comparison of Xstim pacing on global leftventricle function as defined by the change in the maximum rate ofincrease in left intraventricular pressure dp/dt (change inpressure/change in time). The upper graph (FIG. 31A) represents themaximum rate of increase of pressure in the left chamber, specificallythe left ventricle for a plurality of patients, and the dark(er) barsrepresent baseline results and the light(er) bars represent the resultsobtained during Xstim pacing.

While the results shown by the above figures are generally consistent,the results do not track exactly for each patient. It should be notedthat the results of FIG. 30 represent synchrony with only three pointsof the heart, whereas FIGS. 31A and 31B represent a global change inpressure of the left ventricle. As such, FIGS. 31A and 31B represent theeffectiveness on the entire ventricle functions and would generally beconsidered more accurate and less prone to error. FIGS. 31A and 31B showthat patients with low rate of change in baseline functionalitygenerally show improvement when paced with Xstim. Patients with alreadynormal or near normal rate of change generally see little change intheir functionality. The lower graph shows a comparison between baselineand relative amplitudes of Xstim pacing waveforms with respect to therate of change in pressure of the left ventricle.

Without being bound by theory, the Xstim regression line in this graphbeing above the biventricular regression line (biventricular pacing iscurrently being used for implementing Cardiac Resynchronization Therapy(CRT)) suggests that the results obtained with Xstim pacing may providea better way of implementing CRT than biventricular pacing.

FIG. 32 shows the change in maximum pressure rate during biventricularpacing with respect to baseline as a function of the baseline QRS widthin comparison with the response to Xstim pacing. The upper linerepresents a linear representation of Xstim pacing results, with datapoints encircled to differentiate from those corresponding to PATH CHFdata used for the lower line. The lower line, showing PATH CHF data,represents a linear representation of biventricular pacing as published(in tabular format) by Auricchio A., . . . , Spinelli J., et al.,Circulation, 1999; 99:2993-3001.

FIG. 33 shows bursts of Xstim pacing and intrinsic/baseline pacing, aswell as the resulting intraventricular pressure of the left ventricle.The upper wave form shows the ECG readings at RV1 of the intercardiacelectrogram, corresponding to the site that is delivering the Xstimpacing. The bottom wave represents the intraventricular pressure of theleft ventricle. During the five beats of pacing 3304, the ability of theventricle to generate pressure is increased relative to the intrinsicphase 3302.

FIGS. 34 and 35 show the stability of the rate of change in the pressureof the left ventricle during Xstim pacing. The rate of change in thepressure of baseline is also presented over time. The upper linerepresents the absolute level of the maximum rate of change of the leftventricular pressure while pacing with Xstim, whereas the lower linerepresents the same variable but during baseline (without Xstim pacing).

FIGS. 36, 37, 38 and 39 represent the decrease in the maximum rate ofchange in pressure seen when Xstim pacing is stopped. The graphrepresents a continuous timeframe, where the first intrinsic beat hasbeen eliminated. On the left, Xstim pacing was implemented and thenstopped at points 3602, 3702, 3802 and 3902, respectively. The baselinemaximum rate of pressure change was shown on the right. As apparent fromthe figures the maximum rate of change is less for the baseline than itis for the Xstim pacing. FIGS. 36, 37, 38 and 39 represent Xstim pacingwith voltage amplitudes of 5V, 3.5V, 3V and 2.5V, respectively.

FIG. 40 shows the change in the CS activation time relative to the QRScomplex both for the baseline and for Xstim pacing. The left side showsbaseline and right side shows Xstim pacing. Together, the vertical linesand waveforms 4001 and 4002 show the CS activation time. In the baseline(left side) the CS activation time passes through the late part of theQRS complex, whereas for the Xstim (right side) the CS activation timepasses through the early part (or at least earlier part) of the QRScomplex. The waveform region 4003 represents the pacing artifact that ispresent because of the Xstim pacing signal. The waveform region 4004likely represents a signal from the left atrium.

FIG. 41 shows intermittent QRS improvement in narrowing and pressureimprovement for Xstim pacing at 3.5 V. The waveform region 4101represents narrow QRS pulses, and the waveform region 4102 representsone lead (V1) showing a wider/fractionated pulse even though other leadsshow narrow pulse. The region 4103 represents the increase in pressurewhen all leads showed a narrowing pulse. The first half (left side) ofthe waveforms represents Xstim pacing whereas the second half (rightside) represents for baseline functionality. RA1 represents right atrialchannel. RV1 represents the Xstim application channel connected to theXstim lead. LV1 represents the lead located in the posterior lateralregion of the left ventricle. LVP represents the intraventricularpressure of the left ventricle obtained with a millar catheter. Thebottom three waveforms represent lead II, AVR and V1 of the 12 lead ECG.

FIG. 42 shows QRS improvement in narrowing and pressure improvement forXstim pacing at 5 V for the same patient as FIG. 41. This figure showsconsistent narrowing for the QRS width and increased pressure when pacedat 5 V. The first half (left side) of the waveforms represents Xstimpacing whereas the second half (right side) represents baselinefunctionality. Section 4202 shows increased pressure from Xstim pacingrelative to area 4204 without Xstim pacing. RA1 represents right atrialchannel. RV1 represents the Xstim application channel connected to theXstim lead. LV1 represents the lead located in the posterior lateralregion of the left ventricle. LVP represents the intraventricularpressure of the left ventricle obtained with a millar catheter. Thebottom three waveforms represent lead II, AVR and V1 of the 12 lead ECG.

FIG. 43 shows minimum and maximum rate of pressure change (dp/dt)between the Xstim pacing and baseline/intrinsic pacing. Xstim pacing wasdelivered for beat zero to about beat 40; thereafter, Xstim pacing wasnot used. This figure shows the decrease on the bottom of the absolutevalue of the minimum dp/dt, strongly suggesting that Xstim pacing helpsnot only systolic function, which is represented by maximum dp/dt,dp/dt, but also diastolic function, which is assessed here by minimumdp/dt.

FIG. 44 shows the maximum rate of pressure change as correlated to the Rto R interval between beats of the heart. The Xstim maximum rate ofpressure change is higher than the baseline and independent from therate of the heart, particularly for patients with atrial fibrillation.An analysis of the maximum rate of pressure change as a function of theR to R interval can be particularly important for understanding patientswith atrial fibrillation.

While not bounded by theory, the experimental data provides strongsupport that the beneficial effects on cardiac function provided byaspects of the present invention are due, at least in part, to Hisbundle stimulation. The data further supports that, unexpectedly, theHis bundle may react more like a nerve than a myocyte with respect toresponsiveness to electrical stimulation. This may be due in part tofibrotic encapsulation of the His bundle.

It is possible that the success of Xstim pacing can be attributed inpart to the phenomena of anodal break stimulation in tissues with highdirectional anisotropy. It is also possible the success of Xstim pacingcan be attributed in part to a phenomenon sometimes referred to asaccommodation. Accommodation is an increase in voltage thresholdnecessary to produce depolarization of a nerve cell that occurs when thenerve is exposed to a non-zero voltage that is below the thresholdvoltage.

FIG. 45A shows an example procedure for determining placement of a leadfor pacing according to an embodiment of the present invention. Thisprocedure was implemented to place the pacing lead in connection withthe experimental results provided hereafter.

At step 4526, pacing of the heart is accomplished using a lead placed inthe right ventricle and near the His bundle. In a specific instance, thelead includes two electrodes used to deliver oppositely charged pulses,such as with Xstim pacing. At step 4528, heart functionality associatedwith the pacing is monitored. The monitoring can include one or more ofthe following non-limiting examples, ECG readings (e.g., QRS width orfractionation), electrical activity of a late activation site in theleft ventricle, and mechanical contraction of the heart or measurementof the blood flow (e.g., the maximum rate of change in left ventricularpressure). In one implementation, the improved heart function can bebased upon a comparison of heart function without any pacing. Asdiscussed above, it has been discovered that voltages sufficiently abovethe capture threshold can lead to improved heart function relative tovoltages near the capture threshold. Accordingly, one implementation ofpacing uses relatively high voltages (e.g., +/−5V) when pacing todetermine lead location. This can be useful to ensure that the improvedheart function is seen. When the lead is not yet properly placed, pacingcapture can sometimes still be obtained without exhibiting significantimprovement in heart function. Thus, the improved heart function cansometimes be an improvement over heart function resulting from use ofthe pacing lead and pacing profile rather than (or in addition to) thebaseline and/or un-paced heart function.

At step 4530, the lead is repositioned and pacing and monitoring steps4526 and 4528 can be repeated as desired. The results of the monitoringstep can be saved and correlated to the corresponding lead positions. Atstep 4532, the results of the monitoring step 4528 are used to determinethe proper placement for the lead. A few examples of the results of themonitoring step are shown by 4534 (QRS narrowing), 4536 (fractionationimprovement), 4538 (late activation site earlier) and 4540 (mechanicalfunction improved). The lead can then be moved (back) to the leadposition that is selected as a function of the monitoring results.

In another implementation, the steps 4530 and 4532 can be switched sothat repositioning of the lead is done after evaluating the results ofmonitoring step 4528. In this manner, the lead can be repositioned untilsatisfactory results are detected. This can be particularly useful fornot having to record and recreate lead positions previously paced.Instead, once satisfactory monitor results are found, the current leadplacement can be used.

FIG. 45B shows an example procedure for determining placement of a leadfor pacing according to an embodiment of the present invention. At step4502 baseline heart function is recorded (e.g., without Xstim pacing).At step 4504 a lead capable of delivering Xstim pacing is placed nearthe His bundle (i.e., near the root of the septal leaflet of thetricuspid valve in the right ventricle). At step 4506 Xstim pacing isdelivered to the placed lead. In a particular embodiment the Xstimpacing is consistent with the waveforms depicted by and discussed inconnection with FIG. 18. At step 4508 the heart function associated withthe Xstim pacing is recorded. If it is determined, at step 4510, thatXstim pacing improves heart function (e.g., narrowing of the QRS, lessfractionated QRS, improving timing of a late activation site, improvedmechanical function or improved pressure function), the placement of thelead can be selected (and fixed) at step 4512. Otherwise, the positionof the placed lead can be adjusted at step 4514 and steps 4506-4510 canbe repeated as necessary.

In a specific embodiment, the determination step 4510 can be implementedusing multi-lead ECG readings and a probe placed at a late activationsite of the left ventricle (e.g., placing a lead near the posteriorlateral wall of the left ventricle via a catheter inserted through theCoronary Sinus).

Once a desired lead placement has been selected, DDD pacing can beimplemented as shown in step 4516. In a specific implementation, the DDDpacing is implemented with a low atrial rate (e.g., around 50 beats perminute) and an AV delay of around one-half of the baseline or intrinsicAV interval (to allow for full capture and atrial tracking andventricular pacing). In an effort to find an acceptable (or optimize)pacing approach, the DDD pacing is modified to use a variety ofdifferent Xstim pacing profiles as shown in step 4518. As exemplified atstep 4520, one or more of these profiles can be selected from thefollowing non-limiting examples (discussed in terms of a lead with tipand ring electrodes for simplicity), in-phase pulses with positivevoltage applied to the tip and negative voltage applied to the ring,in-phase pulses with negative voltage applied to the tip and positivevoltage applied to the ring, out-of-phase pulses with oppositepolarities applied to respective tip and ring electrodes.

In some instances it may be beneficial to adjust the pacing profile asshown by the determination step 4522. If so determined, the pacingprofile can be adjusted in step 4524. For example, pocket stimulationeffects, dry pocket or other effects due to chronic stimulation canresult in the threshold voltage increasing. It has been discovered thatshifting the overlap duration of the pulses (OD) can help compensate forsuch problems. In another example, the OD can be shifted to allow forlower pacing voltages, even where no dry pocket or other causes arepresent.

FIG. 45C shows an example procedure for determining placement of a leadfor sensing a late activation site in the left ventricle, according toan embodiment of the present invention. As discussed herein, themonitoring of a late activation site of the left ventricle can be usefulfor placement of pacing lead(s) and/or assessment of pacingeffectiveness. The method involves the use of a lead that is capable ofsensing electrical activity in nearby heart tissue. The lead is advancedthrough the coronary sinus until monitoring results from the leadrepresent activation of a late activating region. In one embodiment, thelead can be advanced to a desired spatial position within the coronarysinus. The lead placement can be determined using a number of differentmechanisms, such as fluoroscopy or physical measurements of distance oflead advancements. Each patient, however, may exhibit differentmorphology and/or electrical conduction/activation. Patients who haveconduction abnormalities may exhibit late activation at sites differentfrom patients with normal conduction. Thus, the method depicted by FIG.45C uses electrical measurements taken from the advancing lead todetermine the desired sensing position.

Step 4542 shows that the lead includes multiple sensing electrodes.These sensing electrodes are spatially disparate along the length of thelead. In this manner the most distal electrode represents the electrodethat has been advanced the furthest. The remaining electrodes follow. InFIG. 45D, a simplified version of an example lead is shown by lead 4500.The distal sensing electrode 4550 is followed by sensing electrodes4552, 4554 and 4556.

Once sensing readings are taken from step 4542, a determination is madeat step 4544 as to the relationship between the activation times sensedat the sensing electrodes. In particular, if activation of the distalelectrode 4550 occurs after activation of the other electrodes, the leadcan be advanced further as shown by step 4546. The lead can becontinuously advanced until activation of distal electrode 4550 nolonger occurs before all of the other electrodes. At this point, thecurrent lead position can either be maintained or the lead can beslightly retracted, as shown by step 4548.

Other implementations are possible, such as using a large number ofdifferent sensors. The lead can be advanced a significant distance intothe coronary sinus and a particular sensor can be selected (e.g., byselecting a sensor that shows a late activation relative to the othersensors).

In a specific embodiment of the present invention, the absoluteamplitude of the voltage presented to one of the electrodes can be lessthan the absolute amplitude of the voltage presented to the otherelectrode. This ‘unbalanced’ pacing profile may provide adequate pacing,while helping to control pacing power.

The power consumption of the pacing device can be an importantconsideration. While not bounded by theory, it is believed thatdifferent pacing profiles can be particularly advantageous tocontrolling pacing power. For example, during times that the pulsesapplied to each electrode overlap, the effective voltage seen betweenthe electrodes is believed to be equal to that sum of their amplitudes.During times that the pulses do not overlap, the effective voltage isbelieved to be about equal to the amplitude of the active electrode.Assuming the voltages of the opposite polarity pulses have equalabsolute magnitudes (A), the instantaneous power draw for overlappingpulses is proportional to 4A². The instantaneous power draw fornon-overlapping pulses is proportional to A². For completely overlappingpulses, each having duration T (and thus a total duration of T), thepower drawn is then proportional to 4TA². For completely non-overlappingpulses, each having duration T (and thus a total duration of 2T), thepower drawn is proportional to 2TA². While it has been observed thatnon-overlapping pacing profiles may exhibit pacing thresholds that arearound 0.5 volts higher than those of overlapping pacing profiles, powersavings are still believed to be possible using non-overlapping pulsesin place of overlapping pulses.

FIG. 46 shows a cross-sectional view of a heart and the Hisian andpara-Hisian regions. In particular, FIG. 46 is a view of the right sideof the heart, with the Hisian and para-Hisian pacing areas shown by thedotted lines. These regions represent the general area in which thepacing sites for the experimental data were collected.

FIG. 47 shows a cross-sectional view of the heart marked with pacingsites, according to an example embodiment of the present invention.Representative waveforms for different pacing areas are shown along thesides of the figure. The top left waveform represents a pacing site fora single patient and shows significant atrial (A), Hisian andventricular (V) signals. The middle left waveform represents a pacingsite for 13 patients and shows minor atrial signals with relativelystrong Hisian and ventricular signals. The bottom left waveformrepresents a single patient and shows relatively strong atrium andventricular signals with little Hisian signal. The right two waveformsrepresent a single patient and two patients, respectively, each withprimarily only a ventricular signal.

FIG. 48 shows the location of pacing sites on a three-dimensionaldepiction of the union of the AV node, the parahisian and Hisianregions.

FIG. 49 shows the location of pacing sites on several cross-sectionalviews of the heart. The upper view is a sectional view that includespart of the conduction system that includes the AV node, the His bundleand the right bundle branch. The lower two views show respectiveperpendicular views taken at respective portions of the conductionsystem of the upper view.

FIG. 50 shows an example circuit for providing various stimulationprofiles, according to an example embodiment of the present invention.Switches 5002 and 5008 are enabled to produce a pacing event. Switches5004, 5006, 5010, 5012 and 5014 are set to provide a variety of pacingprofiles. Switches 5004, 5006 and 5014 provide the ability to switchbetween bi-ventricular pacing and single-ventricle pacing (e.g., Xstim).Switches 5010 and 5012 provide the ability to modify the polarity of thepulses applied to the various electrodes.

In a first configuration, switches 5004, 5006 and 5014 are set for Xstimpacing. Switches 5004 and 5014 are connected to the ground (e.g., to thecan or reference electrode). Switch 5106 is connected to switch 5012. Inthis manner both positive and negative voltages are delivered to thering and tip electrodes as determined by switches 5010 and 5012. Whilethe term ring and tip are used in connection with the circuit of FIG.50, the electrodes need not be so limited. For instance, while the tipelectrode is closer to the distal end of the lead, the tip electrodeneed not be located on the distal tip. Moreover, the ring electrodecould be something other than ring as various other electrodeconfigurations are possible.

In a second configuration, switches 5104, 5106 and 5114 are set forbi-ventricular pacing. Switch 5104 is connected to switch 5112. Switch5106 is connected to ground. Switch 5114 is connected the left ventriclelead. In this manner, pacing can be delivered to leads located at bothventricles.

In another configuration, not shown with a figure, a three outputchannel arrangement to facilitate a BiV pacing profile where the LV ispaced with a conventional negative pulse and RV paced with Xstim.

Switches 5110 and 5112 provide the ability to modify the polarity of thevoltages seen between the ring and tip electrodes of the right ventriclepacing lead.

As should be apparent from the various discussions herein, the pacingprofile can include, for example, variations in voltage levels, pulsedurations and phase differences between pulses.

The variations in pacing profiles allow for a number of differentapplications to be implemented. In one such application, the results ofpacing (e.g., QRS width, pressure measurements, synchronicity ofcontracts and the like) are compared between the different profiles.These results can then be used to select the pacing profile (e.g., Xstimor bi-ventricular) that is to be used for the patient.

In another application, the device includes a sensing function to detectthe function of the left ventricle. The sensed function can be used todetermine whether the current pacing profile is adequate and/orcapturing a contraction of the left ventricle. In a specific instance,Xstim pacing is used while sensing heart function in the left ventricle.When the sensed function shows a potential problem (e.g., no capture,wide QRS or other problems) the pacing profile can be adjustedaccordingly. Adjustment of the pacing profile can involve adjustment ofthe voltage. For instance, when partial or complete lack of capture isdetected, the pacing voltage could be increased. Other examplevariations include a change in the polarity of the ring and tipelectrodes or an adjustment of the phase of the applied voltages. In aspecific example, when inadequate left ventricular function is detected,the device can be changed to a bi-ventricular pacing profile. In someinstances, the device can periodically attempt to implement an Xstimpacing profile. If, during the attempt, adequate left ventricularfunction is detected, Xstim pacing can be resumed. Otherwise,biventricular pacing can continue to be implemented.

In yet another application, the device senses atrium function. Thissensed function can be used, for example, to determine the timing forthe ventricular pacing profile. The atrium function can be sensed usingan electrode in the atrium, or using sensing near the His bundle (e.g.,the Xstim pacing lead). When sensing near the His bundle, the sensedfunction can be detected using the ring lead, the tip lead and/or adedicated sensing electrode. In a particular instance, the lead includesa sensing electrode that is closer to the distal end of the lead thanthe ring and tip electrodes. Generally speaking, such placement wouldallow the sensing electrode to be located such that the sensed atriumsignal would be expected to be stronger (e.g., due to placement closerto the atrium).

Cardiac applications represent a specific embodiment of the invention;however, the present invention is also applicable to other therapies,such as those where high current density spot(s) away from theelectrodes are beneficial for stimulating the target including, but notlimited to, nerves, muscle, gastric and intestine system, and cortex.For example, U.S. Pat. No. 5,299,569 to Wernicke et al. issued Apr. 5,1994 (and incorporated herein by reference) is one of a number ofpatents assigned to Cyberonics, Inc. describing pacing the vagus nerveto treat a wide variety of disorders. Pacing electrodes are applieddirectly to the vagus nerve in, for example, the neck. Application of anelectrode directly to the vagus nerve creates risk of mechanical injury(e.g., pressure necrosis) to the nerve. FIG. 20 illustrates use of thepresent invention in such application. Electrodes E₁, E₂ are placedsubcutaneously near (transcutaneously or transvenously coupled) but noton the vagus nerve (VN) in the neck. A reference electrode RE is placedsubcutaneously (transcutaneously or transvenously coupled) on anopposite side of the nerve VN. The electrodes E₁, E₂ and RE areconnected to a pulse generator IPG. With signals as described above, theresulting field F captures the vagus nerve. The signals may be selectedto have amplitude, frequency and other parameters as more fullydescribed in the '569 patent. It will be appreciated that otheralternative examples of using the present invention to pace an organ orthe nerve will occur to one of ordinary skill in the art with thebenefit of the teachings of the present invention.

The skilled artisan will recognize that the various aspects discussed inconnection with the present invention can be implemented in a variety ofcombinations and manners. Moreover, aspects discussed in connection withthe various references disclosed and incorporated herein, includingthose references indicated at the beginning of this document, can beused in combination with aspects of the present invention. In particularto the extent that the references indicated at the beginning of thisdocument include a number of similar figures and related discussions,the skilled artisan would appreciate the interoperability of aspectsdisclosed therein even for figures not common between documents. Thesedocuments provide substantial disclosures throughout which teach aspectsthat can be used in combination with embodiments of the presentinvention, and these documents are thus incorporated by reference intheir entirety. For instance, the U.S. Provisional Patent Applicationidentified by Ser. No. 61/020,511 includes an appendix with figuresdepicting various pacing electrodes and associated circuitry, and suchembodiment(s) can be used in combination with aspects of the presentinvention.

The various embodiments described above are provided by way ofillustration only and should not be construed to limit the invention.Based on the above discussion and illustrations, those skilled in theart will readily recognize that various modifications and changes may bemade without strictly following the exemplary embodiments andapplications illustrated and described herein. Such modifications andchanges do not depart from the true spirit and scope of the presentinvention.

1. An apparatus, comprising: an implantable pacing profile generatorconfigured to generate a specified pacing electrostimulation profile fordelivery to a heart via electrodes located near a septal region of theright ventricle of the heart near the His bundle, the pacing profileincluding: a first pulse for delivery via a first electrode; and asecond pulse for delivery via a second electrode; and wherein the firstand second pulses are at least partially concurrent in time and oppositein polarity to each other.
 2. The apparatus of claim 1, wherein theimplantable pacing profile generator is configured to monitor one ormore of: a QRS width, an electrogram fractionation, a late LV activationtiming, a mechanical synchronicity of a free wall and a septal wall, oran effective throughput.
 3. The apparatus of claim 2, wherein the pacingprofile generator includes a wireless interface configured to allow anexternal device to obtain monitored information indicative of one ormore of: the QRS width, the electrogram fractionation, the late LVactivation timing, the mechanical synchronicity of the free wall and theseptal wall, or the effective throughput.
 4. The apparatus of claim 1,wherein the first and second pulses are substantially identical in timeand duration.
 5. The apparatus of claim 1, further comprising animplantable lead assembly including the first electrode and the secondelectrode.
 6. The apparatus of claim 1, wherein the pacing profilegenerator includes a wireless interface configured to receive a commandto adjust one or more parameters of the pacing profile from an externaldevice in response to monitored information indicative of one or moreof: a QRS width, an electrogram fractionation, a late LV activationtiming, a mechanical synchronicity of a free wall and a septal wall, oran effective throughput.
 7. The apparatus of claim 6, wherein the one ormore adjustable parameters include one or more of a pulse width, a pulseamplitude, or a timing offset between initiation or termination ofrespective pulses.
 8. A method, comprising: generating a specifiedpacing electrostimulation profile for delivery to a heart via electrodeslocated near a septal region of the right ventricle of the heart nearthe His bundle, the pacing profile including: a first pulse for deliveryvia a first electrode; and a second pulse for delivery via a secondelectrode; and wherein the first and second pulses at least partiallyconcurrent in time and opposite in polarity to each other.
 9. The methodof claim 8, comprising monitoring one or more of: a QRS width, anelectrogram fractionation, a late LV activation timing, a mechanicalsynchronicity of a free wall and a septal wall, or an effectivethroughput.
 10. The method of claim 9, comprising wirelesslycommunicating to an external device monitored information indicative ofone or more of: the QRS width, the electrogram fractionation, the lateLV activation timing, the mechanical synchronicity of the free wall andthe septal wall, or the effective throughput.
 11. The method of claim 8,wherein the first and second pulses are substantially identical in timeand duration.
 12. The method of claim 8, comprising receiving, at animplantable medical device, a command to adjust one or more parametersof the pacing profile, the command provided from an external deviceusing a wireless interface.
 13. The method of claim 12, wherein the oneor more adjustable parameters include one or more of a pulse width, apulse amplitude, or a timing offset between initiation or termination ofrespective pulses.
 14. The method of claim 8, comprising adjusting oneor more of the adjustable parameters to improve at least one of: a QRSwidth, an electrogram fractionation, a late LV activation timing, amechanical synchronicity of a free wall and a septal wall, or aneffective throughput.
 15. A processor-readable medium comprisinginstructions, which when executed by a processor included as a portionof an implantable medical device cause the implantable medical deviceto: generate a specified pacing electrostimulation profile for deliveryto a heart via electrodes located near a septal region of the rightventricle of the heart near the His bundle, the pacing profileincluding: a first pulse for delivery via a first electrode; and asecond pulse for delivery via a second electrode; and wherein the firstand second pulses at least partially concurrent in time and opposite inpolarity to each other.
 16. The processor-readable medium of claim 15,wherein the instructions include instructions that cause the implantablemedical device to monitor one or more of: a QRS width, an electrogramfractionation, a late LV activation timing, a mechanical synchronicityof a free wall and a septal wall, or an effective throughput.
 17. Theprocessor-readable medium of claim 16, wherein the instructions includeinstructions that cause the implantable medical device to wirelesslycommunicate monitored information indicative of one or more of: the QRSwidth, the electrogram fractionation, the late LV activation timing, themechanical synchronicity of the free wall and the septal wall, or theeffective throughput.
 18. The processor-readable medium of claim 17,wherein the first and second pulses are substantially identical in timeand duration.
 19. The processor-readable medium of claim 18, wherein theinstructions include instructions that cause the implantable medicaldevice to receive a command to adjust one or more parameters of thepacing profile, the command provided from an external device using awireless interface.
 20. The processor-readable medium of claim 19,wherein the one or more adjustable parameters include one or more of apulse width, a pulse amplitude, or a timing offset between initiation ortermination of respective pulses.